The connection between breast cancer and estrogen has long been recognized. Early researchers noted that removal of the ovaries before the age of 40 reduced the risk of breast cancer by 40%. It is also well established that woman who start their periods earlier or who reach menopause later in life are at higher risk to develop breast cancer since they have more exposure to estrogen over the years. It is believed that each extra year of menarche or menopause increases the risk of breast cancer by approximately 4 percent. Since childbirth also affects estrogen levels, it to can have an impact on breast cancer. It appears that pregnancies reduce the risk of breast cancer. If the first pregnancy occurs before age 20 it can reduce the risk of breast cancer by 50% compared to woman who have their first pregnancy over age 35. In addition woman who have more pregnancies also seem to have less breast cancer. Breast-feeding also seems to reduce the risk of breast cancer.

        The use of oral contraception has been a controversial area in relation to breast cancer risk. The concern is that mammary ductal tissue experiences maximal growth in the later phase of the menstrual cycle under the combined influence of estrogen and progesterone. Since most birth control pills contain both estrogen and progesterone and is given for 21 days out of the month there may be a greater stimulation of the breast tissue than would occur under the natural cycle. Studies are conflicting on whether or not this additional stimulation translates into increased risk. At this time the general opinion seems to be that birth control pills increase the overall risk of breast cancer by a relative risk of 1.5-1.2 for woman under the age of 45. On the other hand it has also been documented that birth control pills reduce the risk of ovarian cancer by 40% and endometrial cancer by 40-60%.

        Since fatty tissue produces estrogen, woman with obesity are also at higher risk to develop breast cancer in the postmenopausal years. Interestingly in premenopausal woman the opposite is true and obesity can actually decrease the risk of breast cancer. The reason for this is not completely clear but may have to do with a negative feedback cycle of estrogens produced in the fatty tissue suppressing ovarian estrogen. In the case of postmenopausal woman the ovaries are already suppressed so the estrogen produced by fatty tissue represents an overall increase of estrogen in the body.
Another very important source of estrogen like exposure is from chemicals that resemble estrogen ( xenoestrogens ). These chemicals have been released into the environment can stimulate estrogen receptors and therefore contribute to the cause of breast cancer. DDT is a pesticide that has been banned but there are still large reserves of it in the environment and it has the capacity to build up in fatty tissue in the body, were in can remain indefinitely. In addition to breast cancer DDT has been found to cause lymphoma, leukemia, respiratory cancer, liver cancer and pancreatic cancer. Besides from DDT there are many other xenoestrogens that are still found in our environment. Manmade plastics used to manufacture containers as well as other products release bisphenol-A. Bisphenol-A is also found in canned foods and in vaginal spermicides and lubricated condoms (it is contained in nonoxynol). If this were not enough, it is also known that Bisphenol is contained in dental sealants and composites. Studies have shown that this carcinogen leaches from treated teeth into the saliva. As much as 950mgm were retrieved from the saliva during the first hour of polymerization. These findings underscore the importance of working with dentists who have knowledge of the biological consequences of the materials they employ. In addition to breast cancer it is feared that this chemical may also contribute to testicular cancer.

        Because of the powerful effects estrogen has on breast cancer, it has been a main focus in treatment. The first hormonal treatments for cancer go back to the nineteenth century when Sir George Beatson preformed oophorectomy (removal of the ovaries) as treatment for metastatic breast cancer. This remained the main hormonal therapy until a number of drugs developed in the second half of the twentieth century were found to reduce the effect of estrogen on breast cancer. With modern methods of detecting estrogen receptors on cancer cells it is possible to determine which woman will best respond to hormonal treatment. However there are limitations to using receptor status as a determinant of response since approximately 25% of woman with positive receptors do not respond and 5% of woman with negative receptors do respond. Another important factor is that as the cancer progresses over time it is common that there will be a reduction in expression of estrogen receptors. Thus a woman that is initially diagnosed with a local tumor and positive receptors may find that as the cancer progresses the cancer produces less receptors and is less responsive to hormonal manipulation.

        Ablative therapy (inducing menopause) may be produced surgically by removing the ovaries, with radiation, by using hormonal LHRH analogues such as Lupron, or with chemotherapy. However, the most common treatment today are the antiestrogens such as tamoxifen. The objective response rate of tamoxifen appears to be comparable to and not significantly better then the previously used ablative therapies.Tamoxifen works by competing with estrogen binding to the estrogen receptor and therefore blocking the effects of estrogen on breast tissue. However because of the similarity of tamoxifen to estrogen it is actually stimulating estrogen receptors in other tissues such as the liver.

        The next question that needs to be addressed is how effective is tamoxifen and what are the risk?

        In regards to clinical effectiveness there has been some controversy. Over the years there have been many clinical trials that have investigated this topic with variable results. In general it is agreed that the overall effectiveness in estrogen receptor negative cancers is quite low. Trials tend to measure 2 types of outcome, recurrence and survival. Of the varius outcomes that can be measured overall survival is the most important, since other outcomes may not correlate with survival. In other words it is possible to use response rate as an objective variable (a response constitutes shrinking a tumor for a specified amount of time) and yet have little or no impact on overall survival. This means that shrinking tumors or decreasing the time to recurrence does not mean the same thing as living longer.

        One paper that reviewed randomized clinical trials reported that tamoxifen can reduce the 10 year recurrence rate by as much as 47% and mortality by 26%. At the outset this sounds fairly positive but when we look at the actual numbers it will be appreciated that the results are not so impressive. This is because results reported as percentages can be manipulated to make the outcome appear better. The report goes on to say that the best results were seen in estrogen positive cases that had lymph nodes involved with cancer. Since overall survival is clearly the most important outcome we will look at some of the results from the studies to get an idea on how effective tamoxifen is in increasing survival.

        Looking at the average results from a number of trials that included all women regardless of receptor statue or involvement of lymph nodes, the following results were obtained:

        For 18,565woman given tamoxifen for 5 years 6346 were alive at the end of 10 years. This compares to 18,534 women who did not receive tamoxifen and of whom 7030 were alive at the end of 10 years. The authors report this as a 22% benefit, but as can be seen from the raw data 25.2% who took tamoxifen were deceased after 10 years as compared to 29.9% in the group that did not take tamoxifen. As can be appreciated by these numbers the absolute results are minimal. The report states that tamoxifen gave the best results in woman who were estrogen receptor positive and also had positive involvement of lymph nodes. Let's see how these women faired. When only woman who had positive lymph nodes and positive estrogen receptor status were included in the analysis the results were only slightly better. In this group 3738 woman received tamoxifen for 5 years and at the end of 10 years 874 (23.4%) were deceased as compared to 1066 of 3689 (28.9%) of woman who did not take tamoxifen. In the study this 5.5% difference is reported as 26% improvement in woman who took tamoxifen. This underlies the importance of looking at the raw data and not just reported percentages.

        The next question is what are the side effects of taking tamoxifen. If side effects are minimal one can justify use even in light of minimal improvements on overall survival. The list of side effects caused by tamoxifen is long. and include: anemia, cataracts, liver toxicity including hepatitis and liver necrosis, hot flashes, suppressed immune function, nausea/vomiting, blood clots, pulmonary embolism, stroke and uterine cancer. Although many of these side effects are life threatening the development of uterine cancer is particularly troublesome. Although nobody knows the exact risk involved one study found a 4-fold increase in endometrial cancer in woman who took tamoxifen for 5 years.. Although not as widely studied it has also been found that tamoxifen can slightly increase the risk of colon cancer.

        Obviously there is more to the story on tamoxifen then many patients realize. Fortunately there are also non-toxic alternatives that may also positively impact the effects of estrogen on breast cancer. Calcium glutarate is an agent that appears to have some influence on breast cancer by aiding in detoxification and the regulation of estrogen. This element is important in detoxification because of its role in the process of glucuronidation. Glucuronic acid is joined to various carcinogens, toxins and estrogen to enable the liver to process and eliminate these compounds. The process is controlled by 2 enzymes. The first one glucuronosyl transferase facilitates the connection of glucuronic acid to the elements, and the second one, beta-glucuronidase reverses the connection.

        The point is to increase the activity of glucuronidation to decrease xenoestrogens in the sytem. Also since estrogen is removed from the body by the same process, increasing glucuronidation will also decrease available estrogen in the body. Studies have shown that calcium glucorate will inhibit the enzyme beta-glucuronidase, which removes glucorate from toxins and estrogen hence decreasing elimination from the body. Studies indicate that calcium gucorate will increase the detoxification of these carcinogens/co-carcinogens by 50% for 5 hours. In rats given carcinogens it has been shown that calcium glucorate can inhibit breast cancer formation by 70% and in rats that did develop tumors, the continuation of calcium glucarate decreased tumor volume by 73%.Although results in animals do not always translate into results for humans they are encouraging.

        Soy has also gained recognition as a phytoestrogen that may be important in the fight against breast cancer. Genistien, a isoflavonoid and phytoestrogen found in soy is believed to be one of the major factors in soy that is active against breast cancer. It was first hypothesized that soy may prevent breast cancer since woman from Asia who consumed large quantities of it had much fewer cases of breast cancer then woman in the west. Also when Asian woman emigrated to the west and adopted western diets their breast cancer rates were similar to westerners. Genistein has been shown to be estrogenic and binds to estrogen receptors and also inhibits cell growth. Since genestine only possesses 1/1000 of the estrogenic activity of estradiol if it binds to an estrogen receptor, it will block estrogens and therefor the cell will not be stimulated by estrogen to the same degree. There has been some fear that since genestine can mimic the effects of estrogen that it may stimulate breast cancer. What is found in cells exposed to genistien is that at low concentrations it may stimulate breast cancer with positive estrogen receptors, but at higher levels it strongly inhibited them from growing. Since genistine also inhibits the growth of cancer cells that do not posses estrogen receptors, it is also believed that genistein is working on another level, in addition to those promoted by estrogen. For instance several studies have shown that genistein can inhibit tyrosine kinase, which promotes various growth factors.

        Some research indicates that it is not only the absolute level of estrogen but the ratio to estrogen and progesterone. It appears that when the relative level of estrogen is higher then progesterone breast cancer is more likely. Premenopausal woman with low progesterone were found to have 5.4 times the risk of developing premenopausal breast cancer. Another study showed that progesterone prevents hyperplasia and increased cell proliferation in the breast caused by estrogens. It is believed that natural and not synthetic estrogens should be used.

        Vitamin D (1,25D3) has been shown to induce differentiation (make them more normal) in cancer cells. Other studies show that 1.25D3 interfered with effects of estrogen in breast cancer. It also appears that vitamin D is most effective on cells that have a higher number of vitamin D3 receptors. Retinoic acid can act synergistically with vitamin D since it causes cells to produce more vitamin D receptors. One study showed increase survival in 136 women with breast cancer who had positive receptors for vitamin D.

        Although there has not been nearly as much research on these non-toxic approaches to controlling the effects of estrogen on breast cancer, it appears that tamoxifen produces at best marginal improvements in survival with major side effects including the possibility of uterine cancer. Most likely if you were to ask an oncologist about the benefit of these non toxic alternatives to tamoxifen, they would tell you there is no proof to justify their use. Yet, as can be seen from the references at the end of this paper there have been numerous studies pointing to the utility of these substances. Of course there still remains much research to be done to further understand and improve on the anti-estrogenic effects of natural hormonal modifiers. In the meantime woman with breast cancer must make important decisions that will affect their lives. I would urge these women to look closely at all the evidence, question their doctors and then to make a decision bases on informed consent, not fear.