Though the 40 percent increased-risk figure in the National Cancer Institute study sounds very scary, here’s what it really means: if you take 100,000 normal-weight women, ages sixty to sixty-four, who are not on hormone therapy, you could expect 350 cases of breast cancer to develop over a five-year period. If all these women took a combination HT consisting of conventional estrogen with progestin, then the number of cases would increase to 560. As you can quickly see, the vast majority of women would not get breast cancer, with or without hormones.
Here’s another way of saying this: statistically speaking, out of 1,000 women who have never taken conventionally prescribed hormones, 77 will get breast cancer by age seventy-five. For women who have taken hormones for five years, that figure climbs to 79; after ten years, it is 83; and after fifteen years, it is 89. Again, the vast majority of women who take hormone therapy (even what I consider a suboptimal form) do not get breast cancer.
The other key point to keep in mind is that virtually all the women in the NCI study—and in most of the other studies that link hormone therapy with breast cancer—were using non-individualized doses of conjugated estrogens (most likely Premarin) in combination with the synthetic progestin Provera. Premarin has been the mostprescribed estrogen in this country for decades, and it is almost always given together with a synthetic progestin such as Provera, often in the combined preparation known as Prempro. In the WHI study, all the women were taking Prempro. Each of these non-bioidentical hormones has its own risks.
Studies have shown that when Premarin is metabolized in the body, its breakdown products are biologically stronger, and therefore potentially more apt to promote cancer, than the breakdown products of bioidentical estrogens.102 It has also been demonstrated that there can be a greater than tenfold variance in blood levels of estrogen among women on the same standard dose of Premarin—usually 0.625 mg.103 What is more disturbing is that many of the women in these studies are on even higher doses, 1.25 mg per day.
Synthetic progestins present their own set of problems. They can bind to both estrogen and androgen receptors in cells and thus stimulate unhealthy tissue growth. They can also increase the biological activity of estrogen. This may explain why women in the National Cancer Institute study who were on both estrogen and synthetic progestin had an even greater risk for developing breast cancer than those women who were on estrogen only.104 This same association has been found in the Million Women Study in the United Kingdom105 and also in the Women’s Health Initiative study. If you are on hormone therapy, you may want to check to see whether or not you are taking anything containing the following synthetic progestins: medroxyprogesterone acetate—MPA (brand names Provera, Amen, Prempro); norethindrone (brand names Femhrt, Activella); or norgestimate (brand name Levlite). If you are, I suggest a change to bioidentical hormones.
A study from Australia that analyzed several studies on HT and breast cancer risk suggests that breast cancer risk linked to estrogen is not as high as assumed. They estimate that the use of HT for about five years starting at age fifty hardly affects the cumulated breast cancer risk up to age seventy-nine. Extended use for ten years increases risk by 0.5 percent and for fifteen years by 0.9 percent. Upon stopping HT, the relative increase in risk quickly declines to zero.106 The same researchers found the same thing with HT use in California.107
What it boils down to is this: HT appears to slightly increase the risk for breast cancer, but not as much as previously thought. It’s probably safer to use bioidentical hormones at individualized doses if you’re going to use HT.
BIOIDENTICAL HORMONES AND CANCER RISK
There is good reason to believe that the long-term use of bioidentical low-dose estrogen, balanced with bioidentical progesterone, would result in a very limited increase in breast cancer risk, if any.108 In fact, one of the largest studies ever done so far that compared risk of breast cancer for women using natural bioidentical hormones with breast cancer risk for women using synthetic hormone therapy showed that the women using natural hormones had significantly less risk of breast cancer.109 The study followed more than 80,000 postmenopausal women for more than eight years. When the same group of French researchers looked at the data to see if the timing of HT made a difference, they published another study the following year that showed no significant increase in breast cancer risk among women using estrogen plus bioidentical progesterone for short durations, no matter when HT use was begun.110
Estrogen
The breasts are glandular organs that are exquisitely sensitive to cyclical hormonal changes in the body. In the first half of the menstrual cycle estrogen tends to increase breast tissue growth; in the second half progesterone stabilizes and refines this growth. During our menstrual periods our breasts are at their smallest, with both hormones at their lowest levels. During perimenopause, which is characterized by estrogen dominance and a relative lack of progesterone, a woman’s breasts may become larger and more tender with no cyclical waxing and waning to keep breast tissue more stable.
For decades numerous studies have demonstrated that, with the exception of phytoestrogens in whole foods, estrogen of all kinds, even that produced by our own bodies, can promote breast tissue growth. In susceptible individuals, this may be associated with an increased risk for breast cancer.111 It is this sensitivity to long-term, uninterrupted estrogen exposure that explains breast cancer risk factors such as early menarche, late menopause, no children, and obesity. Eating a diet that increases insulin also increases hormonal stimulation of breast tissue. Therefore, to preserve breast health, use the least amount of bioidentical estrogen that gives you the results you seek. And get your hormone levels tested when necessary to make sure you’re not getting overdosed.
If you have a family history of breast cancer (grandmother, mother, sister, or maternal aunt) or have the gene for breast cancer, you will probably want to avoid estrogen replacement despite its known benefits.
Opting not to use estrogen doesn’t mean you have to suffer in silence. Many alternatives can relieve your symptoms, improve your health, and also protect your breasts: exercise, dietary improvement, whole soy, herbs, and natural progesterone. These alternatives are very effective.
ESTRIOL: Preliminary studies have shown that women who excrete the highest levels of estriol in their urine appear to have a lower risk of breast cancer. One study from Hebrew University of Jerusalem showed that estriol actually has an antiestrogen effect when given in sufficient dosages, preventing estradiol from binding to estrogen-sensitive tissue, including the breast and endometrium, so tumors don’t form.112 In a recent study from Berkeley, rats receiving a three-week treatment of estriol along with progesterone had a significantly reduced incidence of breast cancer.113 Because of such evidence, many physicians have sometimes used estriol, a non-patentable bioidentical estrogen, in their patients’ hormone therapy regimes. Estriol is biologically weaker than estradiol and estrone, the two other estrogens produced naturally in the body; as already discussed in chapter 9, it works very well when applied locally to estrogen-sensitive tissue such as the vagina. Estriol is widely used in Europe and gives good relief of menopausal symptoms. It is important to note that estriol has been linked with otosclerosis in some women, a genetically linked condition in which three small bones in the middle ear fuse together and thus fail to transmit sound to the brain. Exercise caution with estriol if you have a family history of otosclerosis. Note: The studies on estriol have not been replicated—most likely for financial reasons. Therefore, despite its promise, estriol requires more study.
Progesterone
Though the widely publicized NCI and WHI studies mentioned previously proved synthetic progestin is not protective against breast cancer and may even promote it, their conclusions cannot be applied to the natural, bioidentical progesterone found in such preparations as Pro-Gest cream or Prometrium capsules. In fact, it makes biological sense that adding bioidentical progesterone (which has no androgenic or estrogenic activity) to estrogen
replacement regimens may actually help protect the breasts against overstimulation from estrogen and thus further decrease the risk of breast cancer as long as the dose is low. Bioidentical progesterone has been shown to reduce estrogen-receptor production on breast cells and also to decrease the production of estrogen within breast cells. Some women experience transient breast tenderness in the first week or so of bioidentical progesterone use, since it initially increases estrogen receptors in the breasts. However, this effect is very short-lived and goes away after several days. There is no convincing evidence that low-dose bioidentical progesterone causes continued growth of breast tissue. In fact, it appears to do just the opposite.
Recent research underscores the difference in risk between synthetic and bioidentical progesterone. A 2009 study published in the New England Journal of Medicine concludes that postmenopausal women who take both estrogen and progestin (such as in the form of Prempro) for five years or more have twice the risk of developing breast cancer.114 When the women in the study stopped taking the combination hormone formula, the incidence of breast cancer dropped about 28 percent within the first year. This study was a follow-up to the landmark WHI study, which was stopped in 2002 when researchers concluded that Prempro caused a higher incidence of heart problems and breast cancer. It’s interesting to note that the number of breast cancer cases dropped significantly after 2003. Rowan Chlebowski, M.D., Ph.D., a medical oncologist at Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, conducted a study to determine if this drop in breast cancer cases was due to women halting their hormone therapy or if the drop was due to more vigilant mammography practices. His research indicates that getting regular mammograms didn’t affect the numbers at all, so the effect was indeed related to the hormone therapy—but not to all hormone therapy! Those women who took only estrogen (usually in the form of Premarin) without the progestin were no more likely to develop breast cancer than those women who took no hormones at all. (Women without a uterus typically aren’t given a progestin because it’s deemed unnecessary; these women don’t need to protect their uteruses from uterine cancer.) The synthetic progestin, then, is clearly what accounted for the higher levels of cancer.
It amazes me that nine years have passed since the WHI study, and people are still lumping synthetic progestins and progesterone together without understanding the difference. Most of the medical literature does not even make this distinction! I’ve recommended progesterone instead of progestin for more than twenty years because it matches the hormone made within a woman’s own body far better than any synthetic hormone could. And, as the medical literature now shows, it does not increase the risk of breast cancer.
Genes, Hormones, and Breast Cancer: The Cell
Growth–Cell Death Cycle
If we were to do a very large, long-term study on natural progesterone, we would probably find that it offers some protection to the breast, especially when used without estrogen during perimenopause, when estrogen dominance is so common. The reasons for this have to do with the fact that progesterone plays a role in cell death. Let me explain why this turns out to be a good thing.
Nature in all her wisdom has created a balance between breast tissue cell growth and breast tissue cell death. Breast cancer is one of the health problems that arises when there’s an imbalance between these two processes. Breast cancer—like all cancers, actually—is characterized by two processes: (1) excessive and uncontrolled cell division, and (2) a lack of normal, healthy programmed cell death.115 The signals that direct cell growth, cell development, and programmed cell death (called apoptosis) are directed by the interaction between our genes and our environment. Though this process is extraordinarily complex, we are beginning to understand it, thanks to advances in molecular biology. For instance, we now know that a gene known as the BCL2 gene blocks cell death. This function is appropriate for the times when breast cell tissue needs to grow (such as at puberty and at the ovulatory stage of the menstrual cycle).116 However, when the BCL2 function is not modulated by other factors, it can cause inappropriate cell longevity and possible uncontrolled growth, which can lead to an increased risk of breast cancer. BCL2 is known as a proto-oncogene, which means that it promotes cancer if its expression goes unchecked. (And that depends on its environment.)
Another gene that influences breast tissue is p53. The p53 gene, in contrast to BCL2, is a tumor suppression gene; it halts uncontrolled cell division by increasing apoptosis (cell death). Activation of this gene helps to prevent cell overgrowth and subsequent cancer.
As it turns out, the p53 and BCL2 genes are influenced by sex hormones in ways that either favor cancer or protect against it. Estrogen increases the expression of the BCL2 gene and thus promotes breast cell growth. As I already mentioned, this isn’t necessarily a bad thing. But unabated expression of the BCL2 gene due to excessive amounts of estrogen can result in increased growth of estrogen-sensitive tissue in the breasts, uterus, and ovaries. It is well known that the risk of cancers in these organs is associated with excessive estrogen stimulation.117
In contrast, progesterone decreases the expression of the BCL2 gene while increasing the expression of the p53 gene, leading to an increase in programmed cell death at an appropriate time and thus to a decreased risk of cancer in estrogen-sensitive tissues.118
Estrogen and progesterone also differ in the kinds of breast tissue they stimulate. Estrogen causes breast cells known as ductal tissue to divide and grow. Unopposed estrogen has the capacity to create uncontrolled growth of breast tissue—including cancerous growth. Progesterone, on the other hand, causes the breast cells to differentiate into lobular cells—nature’s preparation for milk production if pregnancy happens. If a woman does not get pregnant, these lobular cells simply undergo programmed cell death, dying off naturally at the end of their life cycle. In other words, a well-differentiated lobular cell is not capable of growing into a cancer.
A very helpful analogy was given to me by David Zava, Ph.D., a researcher with years of experience studying the effects of hormones on breast tissue.119 Dr. Zava likens the different parts of breast tissue to the different parts of a tree. The ductal tissue, whose growth is promoted by estrogen, is like the trunk and branches of the tree. The lobular cells, whose growth is promoted by progesterone, are comparable to the leaves that grow from the ends of the branches. Once a tree cell becomes a leaf, it can never go back to being a trunk or a branch. It simply grows up, matures, and eventually dies at the end of its programmed life cycle. This is not true with the trunk or branches, however. Their cells can grow at any time and make an infinite number of branches or growths on the branches or trunk itself—just like the infinite cell proliferation of a breast cancer.
Given the processes I’ve just outlined, it makes sense that women subject to excessive estrogen stimulation—whether the estrogen is produced in their own bodies (e.g., during periods of estrogen dominance, so common during perimenopause, or from excessive production of estrogen in body fat cells) or is taken in from the outside (through estrogen replacement or through environmental agents with estrogen-like activity)—would be at increased risk for getting breast cancer. But if they take enough progesterone to balance this estrogen, the risk would diminish. And that is precisely what the scientific literature suggests.120
Research by endocrinologist Jerilynn Prior, M.D., founder and scientific director of the Centre for Menstrual Cycle and Ovulation Research (CeMCOR) in Vancouver, British Columbia, shows that women’s estrogen levels are significantly higher than normal during perimenopause. In an effort to counterbalance this, Dr. Prior, also the author of Estrogen’s Storm Season: Stories of Perimenopause (Centre for Menstrual Cycle and Ovulation Research, 2005), successfully prescribes progesterone to her patients with menopausal symptoms. Quelling any concerns that the progesterone will increase risk for breast cancer, Dr. Prior points to studies showing progesterone opposes the effects of estrogen and so may decrease the risk of breast cancer.
For example, a study of women with progesterone deficiency from anovulation, who were being followed at an infertility clinic, has shown those women to have a risk for premenopausal breast cancer 5.4 times greater than those in a control group. And in a 1995 study in which transdermal bioidentical progesterone was placed directly on the skin of the breast, researchers found that the progesterone was able to inhibit breast cell proliferation. The dosages used were approximately the same as when a woman is using a transdermal cream such as Pro-Gest or PhytoGest—in other words, a 2 percent progesterone cream twice per day at recommended dosages. These levels are about equal to those found at ovulation in most women.121
Another study showed that those women who had physiologically adequate levels of progesterone at the time of breast cancer surgery had a decreased risk for recurrence, compared to women whose progesterone levels were low.122 This study has been repeated with the same results, which has led some breast cancer surgeons to suggest that women use 2 percent progesterone cream on their skin for a week or so before breast biopsy or surgery. It appears that bioidentical progesterone can enhance immune response. It also seems to make any tumor cells that may be released during surgery less apt to attach to other sites and grow. This may be why women with breast cancer who are operated on during the luteal phase of their menstrual cycles—when progesterone levels are the highest—have a significantly decreased rate of recurrence.123
A 1996 review of the evidence on progesterone and breast health concluded that bioidentical progesterone not only reduced the rate of spread of breast cancer, but may even be responsible for reducing the incidence of new cases.124
The Wisdom of Menopause Page 67
