The effects of Hormones on Breast Cancer

The Effects of Hormones on Breast Cancer: How to Use Them to Reduce the Risk

Khalid Mahmud, M.D., FACP, ABAAM
Medical Director, Innovative Directions in Health;
Former Medical Director of Oncology, North Memorial Medical Center (Minneapolis, Minnesota USA)

ABSTRACT

Conventional practice of medicine has done very little to prevent breast cancer – the one disease women dread the most. The usual emphasis is on self-exam and mammogram, which is early detection, not prevention. By the time cancer is found on a mammogram it, as a rule, has been slowly growing for up to 15 years. Many factors influence the appearance and growth of cancer cells positively or negatively, and these factors could be manipulated to inhibit the initiation and growth of tiny cancers during this period of time. Hormones are one such factor. The aim of this paper is to consider how different hormones affect breast cancer and how to use them to reduce its risk.

INTRODUCTION

Conventional practice of medicine has done very little to prevent breast cancer – the one disease women dread the most. The usual emphasis is on self-exam and mammogram, which is early detection, not prevention. By the time cancer is found on a mammogram it, as a rule, has been slowly growing for up to 15 years. Many factors influence the appearance and growth of cancer cells positively or negatively, and these factors could be manipulated to inhibit the initiation and growth of tiny cancers during this period of time. Hormones are one such factor (Table 1). The following is a discussion of how different hormones affect breast cancer and how to use them to reduce its risk.

Table 1. Hormones that affect breast cancer

ESTROGENS THAT CAN PROMOTE BREAST CANCER

Estradiol (E2) and Estrone (E1)

It is well known that these two strong estrogens stimulate the growth of breast cancer cells. They do so by acting on the estrogen receptor alpha (ER-alpha) on these cancer cells (Figure 1). ER-negative breast cancer cells are not affected by these hormones.

Figure 1. Cancer Promotion by Estradiol (E2) and Estrone (E1)

Estrogens
Progesterone, Progestins Testosterone
DHEA

Melatonin
Oxytocin
Insulin
Thyroid (Tri-iodothyronine) Human growth hormone

The Importance of E1 and E2 Manufactured by the Breast Fat Cells

Although it is commonly recognized that postmenopausal women with breast cancer tend to have higher blood levels of estrogens,1 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.2, 3 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. (Figure 2).4 The blood level is merely a reflection of the estrogen being generated by the aromatase in the fatty tissues, such as the breast, and not directly involved in stimulating the cancer.

Figure 2. Breast fat cells producing estrogen to fuel cancer growth.

Does Estrogen Treatment for Menopause Increase Risk of Breast Cancer?

Scientific evidence does not support the notion that estrogen treatment for menopause increases the risk of breast cancer. The Women’s Health Initiative (WHI) and Women’s Health Initiative Lund Area, Sweden (WHILA) studies revealed that post-menopausal women receiving estrogen only (without Provera) did not have any increase in the occurrence of breast cancer.5, 6 Only women who had received Provera (PremPro) had an increased risk of breast cancer. In fact, a Swiss HRT study of 23,000 women who were using more natural forms of estrogen (estradiol and estriol) showed an actual 25% decrease in breast cancer risk.7 Furthermore, results of two studies of estrogen use in women with prior history of breast cancer showed a decrease in recurrence rate compared with control subjects.8, 9 The obvious explanation for these findings is that a modest increase in E2 in the blood with estrogen administration does not make any difference to the estrogen level in the breast, which is locally produced and many times higher than what is in the blood. In addition, a study of baboons has revealed that in ovariectomized females (similar to post-menopausal women) estrogen administration causes a sharp and significant drop in the breast tissue aromatase level,10 which should decrease the risk of cancer. This finding suggests that, like in other endocrine systems, the breast fat cells are affected by a negative feedback loop, so that externally administered estrogen actually acts as an ‘aromatase inhibitor’ in the breast, thus explaining the decrease in breast cancer in the larger studies mentioned above.

It should be mentioned that the greatest reduction in breast cancer occurred in the Swiss study where most women received E2 and E3 in more natural forms. The protection has been less obvious in the Premarin studies. This may have to do with the fact that Premarin blocks glutathione S-transferase, an important phase 2 enzyme in the detoxification of carcinogens.11

16 Alpha-Hydroxyestrone (16 alpha-OHE)

16 alpha-hydroxyestrone is an estrogen metabolite that stimulates the growth of breast cancer cells, and has been shown to increase the risk of breast cancer in several studies.12, 13 16 alpha-OHE levels can be lowered by eating less foods containing animal fat and eating more vegetables, particularly the cruciferous varieties, such as broccoli, brussels sprouts, cabbage, and cauliflower.

ESTROGENS THAT INHIBIT BREAST CANCER

Estriol (E3)

There is considerable evidence suggesting that estriol (E3) is protective against breast cancer. Estriol is a weak estrogen that binds to ER-alpha, thus keeping the stronger cancer promoting estrogens, E1 and E2, away from the cancer cells.14 Estriol levels decrease in menopause. Asian women have higher estriol levels than Western women and a lower rate of breast cancer. Women with breast cancer tend to have lower levels of this estrogen.15 Henry Lemmon, a gynecologic 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.16.  Pregnancy is associated with very high levels of estriol and provides protection against breast cancer. A 40-year follow up of 15,000 pregnant women showed that those with the highest pregnancy levels of estriol had a 58% lower rate of breast cancer compared with those that had the lowest levels.17 In the Swiss study cited above, many women received estriol.

Based on such evidence, it makes a great deal of sense to include estriol in hormone replacement therapy preparations. Unfortunately, pharmaceutical estrogen preparations have always excluded estriol.

I believe Biest [E2, 20% + E3 80%] to be the most logical estrogen preparation for women in menopause. Biest should act as an aromatase inhibitor in the breast tissue as well as block ER-alpha to the action of E2. I use Biest cream rather than oral preparations because, unlike oral estrogens,  transdermal preparations do not increase clotting factors and CRP,18 thus reducing the risk of thromboembolism and cardiovascular events. I teach patients to adjust the amount they use and to use just enough to control hot flashes without developing any breast tenderness.

2-Hydroxyestrone (*2-OHE)

2-hydroxyestrone is a good estrogen metabolite. Acting as a week estrogen, it blocks ER-alpha.19 Several studies have shown its protective action, especially the ORDET study (Hormones and Diet in the Etiology of Breast Cancer), an Italian study of 10,760 women.20 2-OHE levels can be increased by eating more vegetables and fruits and less 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. I use it in heavy-set women who do not consume enough vegetables.

Progesterone

I believe that progesterone is an anti-cancer hormone. As well as having anti-breast cancer properties it also has an overall anti-cancer effect. Let us look at the evidence:

  1. In 1981, researchers at Johns Hopkins University reported a 13-33 year follow up on approximately 1000 infertile women. These women were divided into two groups: progesterone deficient women and an all-other-cause of infertility group. The progesterone deficient women had five times more breast cancer than the all-other-causes group. Furthermore, the death rate from all types of cancers was ten times higher in the progesterone deficient group than the other group. 21
  1. Fromby and Wiley from the Sansum Medical Research Institute, California, have performed and reported studies demonstrating that progesterone upregulates p53 (tumor suppressor gene) and downregulates bcl-2 and survivin (tumor promoter genes) in progesterone receptor-positive breast cancer cells, thus resulting in apoptosis of cancer cells.22, 23 These findings have been corroborated by other researchers and reported in the International Journal of Cancer.24
  1. Application of progesterone gel to breast has been shown to reduce mitotic activity in the breast  glands.25
  1. A National Cancer Institute study revealed that premenopausal women with the highest third week-of-cycle progesterone levels had a 60% decrease in subsequent breast cancer compared with those who had the lowest levels.26 A French study from International Agency for Cancer

Research showed the same results.27

  1. Breast cancer surgery studies reveal that surgical treatment during the follicular part of menstrual cycle (low progesterone levels) results in higher metastases and death rate compared to surgery during the luteal part (higher progesterone levels) of the menstrual cycle.28
  1. 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.29

It must be emphasized that only natural bioidentical progesterone has these anti-cancer effects, not the artificial progestins such as Provera (Medroxyprogesterone). Unfortunately, the majority of medical literature does not distinguish between bioidentical and artificial progesterone. Many practitioners of medicine tend to brush these differences aside with statements like: “a hormone is a hormone is a hormone – they are all the same.” To understand such beliefs, one has to go back into the history of steroid hormone discovery and synthesis (Figure 3).

In the 1930s, Russel Marker, a brilliant 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 ridiculed in the United States, so he moved in with a small Mexican lab and started producing bioidentical progesterone on a large scale. Subsequently, other bioidentical hormones, such as testosterone and estrogen could be produced.

O

Cholesterol

CH3

CH3

CO
OCOCH3

Medroxyprogesterone (PROVERA)

Russel Marker

O C CH3 C O C CH

OOO

Norethindrone (Ortho Micronor)

Progesterone O

O
T estosterone

O

OH (Estriol)

HO

Estradiol

Figure 3. Natural and artificial hormones.

When the large US drug companies got into the action, there was no profit motive in marketing the bioidentical, or real hormones, as these hormones could not be patented. The drug houses therefore modified the molecules to create artificial hormones, which are patentable drugs, and marketed those to US physicians as hormones. They called drugs like Provera “Progestins” and made the physicians believe that it was the same thing as progesterone. Similarly, Premarin, a horse estrogen was marketed as a replacement for human estrogen despite the fact that the molecules are very different.

The pharmaceutical companies should have known that a minimal change in the natural molecule – like the minimal change that turns progesterone into testosterone, and testosterone into estrogen – changes the entire action and function of the molecule, and that these molecules act in the human body only by attaching to their specific and exact receptors (Figure 4). Yet, they proceeded to blur the difference between the real and the artificial and proceeded to market these substances to US doctors and US women.

Figure 4. Steroid hormones working in the nucleus of the cell.

Many billions of dollars worth of these “hormones” were sold to women for many years until the WHI studies showed that these drugs resulted in increased cardiovascular complications, strokes, dementia, and breast cancer. Most of these complications appear to be related to Provera (medroxy- progesterone), which has been demonstrated to cause endothelial damage, inflammation, and insulin resistance,30-32 all of which increase the risk of cardiovascular problems, strokes, dementia, and cancer. Real progesterone is protective against these problems.

It must be mentioned that the same companies also manufacture real, “bioidentical”, hormones under government regulations, and sell them to compounding pharmacists who can mix and dispense these according to physician’s orders for individual patients, and much less expensively. It is up to the physicians to learn how to prescribe the real hormones. Unfortunately, most physicians do not have the time or the desire to do so.

Testosterone

Testosterone exerts a direct anti-breast cancer effect. An NIH study clearly demonstrated that testosterone reduced the ER-alpha activity on breast cells in monkeys and reduced the proliferation rate of the cells.33 Researchers at the University of Calabria in Italy have shown that testosterone inhibits breast cancer cells through its own androgen receptor, AR.34 A recent report on 624 breast cancer patients at the National Cancer Institute has indicated that testosterone or DHEA levels did not increase the risk of breast cancer.35

However, it is important to point out that testosterone can get converted into estrogen by aromatase in the breast tissue, and some reports suggest that women with higher estrogen plus testosterone have more breast cancer. So, what is the bottom line? I believe that menopausal women should receive testosterone, if their levels are low and symptomatic, but only in small doses, and in the form of testosterone creams. I monitor their testosterone levels and make every effort not to exceed their levels beyond the 60th percentile. I do not believe in giving women testosterone injections as they lead to high peak levels of testosterone and potentially high conversion to estrogen in the fatty tissues such as the breast.

DHEA

breast cancers transplanted on to mice.38 Patients with low DHEA levels and breast cancer have more metastases.39 Low DHEA levels have been associated with higher breast cancer risk in pre-menopausal women, conversely, high DHEA levels have been associated with more post-menopausal breast cancer.40 It has been shown that if one infuses a large amount of DHEA into Petri dishes containing breast cancer cells, after about 4 days some of it eventually gets converted into estrogen, which can stimulate breast cancer cells.41 I recommend that women with low DHEA levels receive DHEA, but with caution, and only with blood level monitoring to ensure that you do not to exceed the 60th percentile of the reference range.

Melatonin

Melatonin is not just a sleep hormone. It plays a major role in the integrity of the neuroendocrine and immune systems. Melatonin levels begin to drop after the age of 15. By the time we reach our 60th birthday we have only one-tenth of our youth levels of melatonin.

Melatonin has multiple anti-cancer effects (Figure 5). It upregulates p53 and p21 tumor suppressor genes and reduces the concentration of ER-alpha on the tumor cells.42 Linoleic acid (LA) can promote cancer cell growth. Melatonin has been shown to block the entry of LA into cancer cells.43, 44 Melatonin protects cells against the effect of radiation.45 It also increases superoxide dismutase (SOD), glutathione, and catalase levels in cells, thus protecting them from cancer promoting free radicals.46 Melatonin also has anti-inflammatory properties,47 and thus may also help to prevent cancer by combating inflammation.

Blind women have higher levels of melatonin and a significantly lower rate of breast cancer than non-blind women.48 Conversely, night shift workers such as nurses, radio-telephone operators, and flight attendants tend to have lower melatonin levels and higher rates of breast cancer.49 Some studies have now appeared showing that the addition of melatonin to conventional treatments of cancer result in superior results.50 I believe melatonin should be given to all women having sleep difficulties, especially those at higher risk for breast cancer.

DHEA inhibits the growth of breast cancer cells in mice.36, 37 It also inhibits the growth of human

Free Radicals LA* Inflammation Radiation Cancer Cell

Oxytocin

Mechanisms of Melatonin Anti-Cancer Action

*LA: Linoleic Acid *ER-a: Estrogen Reception-alpha

Figure 5. Inhibitory effects of melatonin on breast cancer.

Oxytocin is the pituitary hormone that lets the milk down in lactating mothers. It also has anti- cancer effects. It contracts the milk ducts thus propelling the free radical laden fluid out of the ducts. Free radicals in this fluid have been implicated in the initiation and stimulation of cancer.51 Oxytocin inhibits many types of cancer cells through its own oxytocin receptor (OR) on these cells.52 It also inhibits ER-alpha.53 Studies from many countries have shown that breastfeeding reduces the risk for breast cancer.54 Most likely this benefit is due to higher oxytocin levels during lactation. It makes a great deal of sense to breastfeed babies as long as possible, not just for breast cancer prevention but also for many other benefits to mother and child.

Oxytocin is not only increased with breastfeeding but also with breast and nipple stimulation. A

10-minute stimulation increases oxytocin levels by 100%.55 Alcohol tends to block this release of oxytocin. Frequent breast and nipple stimulation, performed hygienically, seems to make sense and may reduce the risk of breast cancer.56

Insulin

By acting as a growth factor insulin promotes cancer cells by increasing levels of tyrosine kinase.57 A Vanderbilt study has shown that women with higher insulin levels are more likely to develop breast cancer.58 Whilst other studies have demonstrated that breast cancer patients with high insulin levels have more metastases.59 Finally, the large Nurses Health Study has revealed a higher incidence of breast cancer in the presence of diabetes.60 I believe insulin resistance (metabolic syndrome) should be managed and controlled before the onset of frank diabetes. It will not only reduce breast cancer and other cancers, but also reduce hyperlipidemias, hypertension, and cardiovascular events. I use agents like chromium or metformin in addition to appropriate nutrition and exercise to achieve these ends.

Tri-iodothyronine (T3)

T3 has many unappreciated anti-cancer effects. As we age our natural killer (NK) cells (the first  defense against cancer cells) decline. T3 increases NK cell activity.61 It increases interleukin-2 (IL-2), an important cytokine in the defense against cancer, which has been used effectively in many cancer treatment protocols.62 Tenacin C, a proliferative protein in cancer cells, is inhibited by T3.63 Cyclin D1 and Cyclin T1 genes are turned on in breast cancer cells. T3 suppresses these genes.64 It has been shown to directly inhibit MCF-7 (common type of breast cancer cells) in tissue cultures,65 to decrease aromatase in breast cancer cells,66 and to increase oxytocin production which inhibits cancer cells.67 T3 also increases sex hormone binding globulin (SHBG), which has an anti-breast cancer effect.68 T3 is also involved in DNA repair, which is important for our defense against cancer.69 Hypothyroidism is associated with increased breast cancer risk.70 It is T3 and not T4 or TSH that has anti-cancer activity. Unfortunately, most physicians check TSH and maybe T4, but not T3. Synthroid contains T4 only, and does not increase T3 adequately in many patients. Armour thyroid has both T3 and T4 in more natural proportions. I prefer to give my patients Armour thyroid, and I monitor their T3 levels regularly.

Human Growth Hormone (HGH)

HGH increases the production of insulin-like growth factor (IGF), which, like insulin, can stimulate  the growth of cancer cells.71, 72 However, HGH has many anti-cancer actions (Figure 6). 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.73 HGH repairs DNA damage inflicted to cells by carcinogens and radiation.74 It increases the activity of NK cells.75 It stimulates the thymus gland and modulates the secretion of thymic hormones, improving the overall immune response.76, 77 Its effect on the function of monocytes is inhibitory to cancer cells.78 Nuclear Factor Kappa B (NFKB) is a proliferator of cancer cells. HGH inhibits NFKB in cancer cells by increasing glutathione.79 It also increases levels of vitamin D, which has been shown to be inhibitory to cancer cells.80 Low-dose HGH therapy, unlike high-dose HGH therapy, has been shown to reduce visceral fat and actually improve insulin resistance,81 which should have an anti-cancer effect.
Unfortunately, the academia accentuates the one cancer stimulatory effect of HGH, but fails to mention any thing about its multiple anti-cancer effects. Studies of HGH administration to adults have not shown cancer as a risk.82 Recently, a western clinic that had treated some 2000 adults with HGH over several years communicated the results at the annual A4M meeting. There had been only one case of cancer. Acromegalics with sky-high HGH levels do not have increased rates of cancer; except for a somewhat higher risk for colon cancer.83 They do not have any increase in the rate of breast cancer. I do not believe that HGH therapy should be withheld for fear of cancer if clear cut indications for such therapy exist.

Figure 6. Effects of HGH on Breast Cancer.

CONCLUDING REMARKS

Many factors influence the appearance and growth of cancer cells positively or negatively, and these factors can be manipulated to inhibit the initiation and growth of tiny cancers during this period of time. There are a number of things that you can do to help reduce your patient’s risk of developing breast cancer:

  • For HRT use only bioidentical hormones
  • For estrogen use Biest [4:1 ratio of E3 to E2]. Monitor patient and blood levels. Control hot flashes, but avoid breast tenderness. If breast tenderness develops back off on the dose. It may mean that the breast is not manufacturing much estrogen and the treatment E2 is entering the breast more than desired amounts. Use cream rather than oral preparations, thus avoiding an increase in clotting factors and c-reactive protein. Also, cream dose is easier to adjust.
  • Increase 2/16 E ratio by encouraging patients to eat more vegetables and fruits, and less animal fat. Give Indole 3 Carbinol to patients with a high risk of breast cancer.
  • Avoid Provera. Use only natural bioidentical progesterone.
  • In pre-menopausal women with PMS, check E2 and progesterone levels on day 21 of cycle. If there is E2 dominance or Progesterone deficiency, give progesterone from day 14-28 of cycle. You will relieve PMS and very likely reduce the risk of breast cancer.
  • In women with DHEA or T deficiency use DHEA or T cream and monitor levels not to exceed 60th percentile of the reference range.
  • Treat insulin resistance rather than waiting for frank diabetes to develop (nutrition, exercise, chromium, DHEA, metformin, etc.)
  • Increase oxytocin levels (breastfeeding, breast and nipple stimulation, alcohol reduction).
  • Pay attention to free T3 in patients with symptoms of hypothyroidism. Use Armour thyroid rather than Synthroid when needed.
  • Don’t be afraid to use HGH for fear of cancer, when clear indications for HGH exist.

REFERENCES

  1. Mady EA, Ramadan EE, Ossman AA. Sex steroid hormones in se
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