Hormones and breast cancer: can we use them in ways that could reduce the risk?
 

Khalid Mahmud – June 2008

Abstract
 

Many hormones promote or inhibit breast cancer in different ways. These effects and the mechanisms involved are reviewed in order to suggest a potentially safer use of hormones. Natural estrogens, administered transdermally, and natural progesterone may be the safest combination of female hormones. Increased intake of cru­ciferous vegetables could provide additional safety by improving 2-hydoxyestrone and diminishing 16 alphahy­droxyestrone. Testosterone and dehydroepiandrosterone (DHEA) may directly inhibit breast cancer, but could potentially stimulate it by being aromatized into estrogen in the breast. Modest doses with blood level monitoring.
 

Introduction

Conventional thinking about hormones and breast cancer does not extend much beyond estrogen, which is viewed by most medical practitioners, and their patients as a culprit. In fact, many hormones affect breast cancer and in different ways, both positively and negatively. An appreci­ation of these effects may help us use hormones more effec­tively. This paper reviews the effects of hormones on breast cancer and offers suggestions as to how to use them while minimizing the risk. 
 

Estrogens that can promote breast cancer

Estradiol [E2] and Estrone [E1] and the mechanism of promotion. E2 and E1, two strong estrogens, are well-known to stimu­late the growth of breast cancer by acting through the estrogen receptor alpha [ER-alpha] on malignant cells. ER negative breast cancer cells are not affected by these hormones. Although it is recognized that post-menopausal women with breast cancer tend to have higher blood levels of estrogens, what is generally not appreciated is the fact that post-menopausal women have much higher levels of these estrogens in the breast: 10 to 50 times higher than in the blood. Fat cells around a post-menopausal breast cancer have been found to have high aromatase activity, generating estrogen locally to fuel the growth of cancer. In other words, it is the high concentration of estrogen produced in the breast which is instrumental in stimulating cancer cell growth. Blood levels are merely a reflection of what is happening in the breast.

Menopausal estrogen replacement and risk of breast cancer

 
Contrary to common beliefs, scientific evidence suggests that estrogen therapy in menopause does not increase the risk of breast cancer, and may even reduce it. The Women’s Health Initiative (WHI) and Women’s Health Initiative Lund Area, Sweden (WHILA) studies revealed that women receiving estrogen only (without provera) did not have any increase in the occurrence of breast cancer, and may actually have had a slight decrease in risk. Only women who had received provera (PremPro) had an increased risk. A Swiss HRT study of 23,000 women, most of whom were using estradiol or estriol rather than equine estrogen, showed an actual 25% decrease in death rate from breast cancer. Two studies of estrogen use in women with prior history of breast cancer conducted at the MD Anderson Cancer Center showed a lower recurrence rate compared with the control subjects. Three additional reports of 174, 125 and 286 patients who received HRT after breast cancer, also revealed lower recurrence rates compared with the control subjects. A likely reason for these findings is that a modest increase in E2 in the blood with estrogen administration should not have a detrimental effect on the estrogen concentration in the breast, which is locally produced and already many times higher than that in the blood. Furthermore, a study of ovariectomized baboons (reproducing a condition similar to that of menopausal women) has demonstrated a sharp and significant drop in the breast tissue aromatase following estrogen administration, suggesting the existence of an endocrine type negative feedback loop. The extraneously administered estrogen may, therefore, provide protection rather than cause harm, which would explain the reduced recurrence in the above mentioned studies. It should be added that, among the reports on women without breast cancer cited above, the greatest reduction in risk was observed in the Swiss study, where most women received E2 and E3 in more natural forms. The protection has been less obvious or absent in studies utilizing equine estrogens. This may have to do with the fact that premarin blocks gluthione S-transferase, an important phase 2 enzyme in the detoxification of carcinogens.

16 alpha-hydroxyestrone

This estrogen metabolite stimulates the growth of breast cancer cells and has been shown to increase the risk in several studies. It can be decreased by reducing the intake of animal fat in the diet and increasing that of vegetables, particularly the cruciferous varieties, such as broccoli, brussels sprouts, cabbage, and cauliflower.

Estrogens that can inhibit breast cancer

 
Estriol

There is evidence to suggest that estriol is protective against breast cancer. It is a weak estrogen that binds to ER-alpha, thus denying entry to the stronger estrogens, E1 and E2. In menstruating women, estriol amounts to 80% of the blood estrogens. Its levels decrease in menopause. Asian women have higher estriol levels than Western women and lower rates of breast cancer. Women with breast cancer tend to have lower levels of estriol. Henry Lemmon, GYN oncologist at the University of Nebraska, spent years studying estriol. He was able to prevent the induction of carcinogen and radiation induced breast cancer in animals by using estriol. Pregnancy is associated with very high levels of estriol and provides protection against breast cancer. A 40-year follow-up of 15,000 Kaiser Permanante female pregnant patients showed that women with the highest pregnancy levels of estriol had a 58% lower breast cancer rate than the group with the lowest levels.

2-hydroxyestrone

This is a good estrogen metabolite. Acting as a weak estrogen, it blocks ER alpha. Several studies have shown its protective action, especially ORDET, the “Hormones and Diet in the Etiology of Breast Cancer: an Italian study of 10,760 women”. 2- hydroxyestrone can be improved by increasing intake of vegetables and fruit, and minimizing animal fat. Indole 3-Carbinol, an extract of broccoli, has been shown to increase its levels and is a popular supplement for the prevention of breast cancer.

How to use and manipulate estrogen in menopausal women

Based on the scientific evidence discussed above, it appears logical to use a combination of natural E2 and E3. Pharmaceutical preparations containing natural E2 are available (patches, tablets, vaginal preparations) but so far have not included E3. A combination (20% E2 + 80% E3) called Biest can be mixed by compounding pharmacists in the United States and is the preferred choice of this author. It is available as a transdermal cream which is ideal. Unlike oral preparations of estrogens, it does not increase clotting factors and CRP due to the first pass liver effect, thus reducing the risks of 6 thromboembolism and cardiovascular events. Also, patients can be shown how to use just enough cream to control symptoms and avoid excessive amounts, which could cause bloating, breast tenderness or bleeding. Furthermore, with the use of natural estrogen, blood levels can be monitored and kept within a modest range. Dietary changes to increase 2-hydroxyestrone and reduce 16-alpha-hydroxyestrone should be suggested to patients when appropriate. Progesterone Progesterone appears to be an anti-breast cancer hormone. In fact it may have an overall anti-cancer effect. The following evidence supports the existence of such an effect.

1. In 1981, researchers at Johns Hopkins University reported a 13–33 year follow-up of approximately 1,000 infertile women. The women were divided into two groups: the progesterone deficient women and those with non-hormonal causes of infertility. The progesterone deficient women had five times more breast cancer, and 10 times higher overall cancer mortality than the other group.
2. Fromby and Wiley from the Sansum Medical Research Institute, California, have performed and reported studies demonstrating that, in progesterone receptor positive breast cancer cells, progesterone up-regulates p53 (tumor suppressor gene) and down-regulates bcl-2 and survivin (tumor promoter genes) resulting in apoptosis (cell death) of cancer cells. These findings have been corroborated by other researchers.
3. Application of progesterone gel to the breast has been shown to reduce mitotic activity in the breast glands.
4. A National Cancer Institute (Milan, Italy) study revealed that pre-menopausal women with highest 3rd week-of-cycle progesterone levels had a 60% decrease in subsequent breast cancer compared with those who had the lowest levels. A French study from International Agency for Cancer Research showed the same results.
5. Breast cancer surgery studies reveal that surgical treatment during the follicular phase of menstrual cycle (low progesterone levels) results in higher metastases and death rates than surgery during the leuteal phase (higher progesterone levels).
6. A large 2005 French study of 54,548 menopausal women revealed that women who took estrogen and provera had a 40% increase in breast cancer. However, those who took estrogen and natural progesterone had a 10% decrease.

It must be emphasized that “only natural or endogenous progesterone has these anticancer effects,” not the pharmaceutical progestins such as medroxyprogesterone. Unfortunately, most medical literature does not distinguish between natural and artificial progesterone and most medical practitioners believe that progestins and progesterone are the same thing. To understand why this has happened, it may be helpful to go back into the history of steroid hormone discovery and synthesis. In the 1930s, Russel Marker, a scientist at Penn State University, set out on a quest to manufacture exact replicas of human steroid hormones by a process of degeneration of similar molecules in plants. Eventually, he found one such molecule in the Mexican Yam that could be chemically degraded to produce an exact copy of human progesterone. His discovery was ignored in the United States. He moved to a small Mexican laboratory and started producing “bioidentical progesterone” on a large scale. Subsequently, other bio-identical hormones, such as testosterone and estrogen could be produced (as happens in the human body where progesterone converts into testosterone and then into estrogen) by minimal changes in the molecule. When the large US drug companies became involved, they had to bypass the natural molecules and create pharmaceuticals that were structurally different from the natural molecules and which could, therefore, be patented. Provera (medroxyprgesterone) was thus introduced as a “progestin” and marketed to physicians, who came to believe that it was the same thing as progesterone. Similarly, premarin, a horse estrogen was marketed as a replacement for human estrogen, knowing that these substances are different from endogenous hormones. In fact, a minimal change in the natural molecule (e.g., progesterone to testosterone to estrogen) changes the entire action and function of the molecule. The pharmaceutical hormones were marketed to US physicians and women, and over the years, sales climbed to billions of dollars until the WHI studies revealed increased cardiovascular complications, strokes, dementia, and breast cancer. Very likely some of these complications were related to the equine estrogens (as mentioned above) but most appear to have been related to medroxy-progesterone, which is known to cause endothelial damage, inflammation and insulin resistance all of which in turn increase risk of cardiovascular problems, strokes, dementia, and cancer. Real progesterone does not cause these problems. It must be mentioned that the same pharmaceutical companies also manufacture real, bio-identical hormones, and supply them to compounding pharmacists who can mix them according to physician’s orders for individual patients – at a much lower cost. It is this author’s practice to prescribe natural progesterone for all menopausal women receiving estrogen therapy, and not just for those who have had a hysterectomy.

Testosterone

Testosterone exerts a direct anti-breast cancer effect. An NIH study demonstrated that testosterone decreased the ER alpha activity on breast cells in monkeys and reduced the proliferation of these cells. At the University of Calabria, Italy, researchers have shown that testosterone inhibits breast cancer cells through its own androgen receptor, AR. A recent report on 624 breast cancer patients at the National Cancer Institute has indicated that testosterone or DHEA levels did not affect the risk of breast cancer. None the less, it is important to point out that testosterone can be aromatized into estrogen in the breast tissue. It, therefore, seems prudent to use testosterone for symptom management in small doses as creams, to followup with blood level monitoring and to avoid high blood levels. Testosterone by injection which results in high peak levels could potentially lead to increased conversion into estrogen in the breast.

DHEA

DHEA inhibits the growth of breast cancer cells in mice. It also inhibits the growth of human breast cancers transplanted onto mice. Patients with low DHEA levels and breast cancer tend to have more metastases. Low DHEA levels have been associated with higher breast cancer risk in pre-menopausal women; however, high DHEA levels have been associated with a higher incidence post-menopausal breast cancer. It has been shown that if one infuses a large amount of DHEA into Petri dishes containing breast cancer cells, after about four days some of it is eventually converted into estro-gen, which can stimulate breast cancer cells. Again, careful management of the administration of DHEA to women with low levels of this hormone represents a prudent approach along with blood level monitoring to maintain levels within a modest range.

Melatonin

Melatonin is not just a sleep hormone, it plays a major role in the integrity of the neuroendocrine and immune systems. It begins to decline at an early age; by age 60 we have only one tenth of what we had at age 15. Melatonin has many anti-cancer effects. It up-regulates p53 and p21 tumor suppressor genes and reduces the concentration of ER alpha on the tumor cells. Linoleic acid [LA] can promote cancer cell growth. Melatonin blocks the entry of LA into cancer cells. Melatonin protects cells against the effect of radiation. It increases superoxide dismutase (SOD) glutathione and catalase in the cells thus protecting them from cancer promoting free radicals. Inflammation promotes cancer cell growth. Melatonin has an antiinflammatory effect. Blind women have higher levels of melatonin and lower than normal rates of breast cancer. On the other hand, night shift workers such as nurses, radio-telephone operators, and flight attendants tend to have lower melatonin levels and higher rates of breast cancer. Some studies have now shown that the addition of melatonin to conventional treatments of cancer results in superior outcomes. Melatonin, in physiological doses, should be considered for all women suffering from insomnia, especially those at a higher risk of breast cancer.

Oxytocin

Oxytocin, a pituitary hormone leads to milk ejection in lactating mothers. It also has anti-cancer effects. Free radicals in the milk duct fluid have been implicated in the initiation and stimulation of cancer. Melatonin contracts these ducts to propel the fluid out. It inhibits many types of cancer cells through its own oxytocin receptor (OR). It inhibits ER alpha. Studies from many countries have shown that breast feeding reduces the risk of breast cancer. Most likely this benefit is due to higher oxytocin during lactation. It makes sense to breast feed babies as long as possible, not just for breast cancer prevention but also for the many other benefits. Oxytocin is not only increased with breast feeding but also with breast and nipple stimulation. A ten minute stimulation increases oxytocin level by 100%. Alcohol tends to block this release of oxytocin. Frequent breast and nipple stimulation, performed hygienically, could therefore be protective, and has been advised to reduce the risk of breast cancer.

Insulin

Acting as a growth factor, insulin promotes the cancer cells by increasing tyrosine kinase. A Vanderbilt study has shown that women with higher insulin levels have more breast cancer. Other studies have demonstrated that breast cancer patients with high insulin levels have more metastases. The large Nurses Health Study has revealed a higher incidence of breast cancer in the presence of diabetes. Insulin resistance (metabolic syndrome) should be managed and controlled before the onset of frank diabetes. It would not only reduce the risk of breast cancer and other cancers, but also reduce hyperlipidemias, hypertension and cardiovascular events. Agents like chromium or metformin, in addition to appropriate nutrition and exercise, can help achieve these ends.

10 Tri-iodothyronine [T3]

T3 has several unappreciated anti-cancer effects. As we age, our “Natural Killer Cells” (the first defense against cancer cells) decline. T3 increases NK cell activity. It increases interleukin-2, an important cytokine in the defense against cancer, which has been used effectively in many cancer treatment protocols. “Tenacin C”, a proliferative protein in cancer cells, is inhibited by T3. Cyclin D1 and Cyclin T1 genes are activated in breast cancer cells. T3 suppresses these genes. It has been shown to directly inhibit “MCF-7” (a common type of breast cancer cells) in tissue cultures, to decrease aromatase in breast cancer cells and to increase oxytocin production which inhibits cancer cells. T3 also increases “Sex Hormone Binding Globulin” (SHBG) which has an anti-breast cancer effect. It is involved in DNA repair, which is important for our defense against cancer. Hypothyroidism has been associated with increased breast cancer risk. It is T3 and not T4 or TSH that has anti-cancer activity. Usual thyroid testing consists of TSH and T4, but not T3. Most hypothyroid patients are treated with synthroid, which is T4 only, and may or may not increase T3 levels adequately in different patients. Armour Thyroid has both T3 and T4 in more natural proportions and should be considered in patients with sub-optimal T3.

Human Growth Hormone

HGH increases the production of “Insulin Like Growth” factor [IGF] which, like insulin, can stimulate the growth of cancer cells. However, HGH has many anti-cancer actions. HGH administration increases IGFBP-3, a protein which binds IGF. IGFBP-3 inhibits estrogen induced proliferation of breast cancer cells as well as promoting apoptosis of cancer cells. HGH repairs DNA damage inflicted on cells by carcinogens and radiation. It increases the activity of “Natural Killer Cells”. It stimulates the thymus gland and modulates the secretion of thymic hormones, improving the overall immune response. Its effect on the function of monocytes is inhibitory to cancer cells. “Nuclear Factor Kappa B” is a proliferator of cancer cells. HGH inhibits NFKB in cancer cells by increasing glutathione. It increases levels of vitamin D, which is inhibitory to cancer cells. Low-dose HGH therapy, unlike high doses, has been shown to reduce visceral fat and actually improve insulin resistance, which should have an anti-cancer effect. Studies of HGH administration to adults with HGH have not shown cancer to be a risk. Acromegalics, with high HGH levels, do not have increased rates of cancer, except for a slightly higher risk of colon cancer. They do not have a higher risk of breast cancer. HGH should only be given when there are clear indications, and not as a performance enhancement drug. When indicated, it should not be withheld for fear of cancer. To summarize, many hormones effect breast cancer, positively or negatively. An understanding of these effects and their mechanisms can help us use different hormones judiciously and in ways that could potentially reduce or minimize the risk of breast cancer.