estrogen and breast cancer

Estrogen And BreastCancer

James S. Nagel, M.D.


3

“Does not Dionysius seem to have made it

sufficiently

clear that there can be nothing happy

for the person over whom some fear

always looms?”

Cicero

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“The fear of hormone replacement therapy, like the Sword of

Damocles, looms over the head of all who dare use and or

prescribe Estrogen replacement therapy.”


• Everybody knows estrogen causes breast cancer.

• The media reports about the Woman’s Health Initiative (WHI) have been abundantly clear.

• The message is estrogen causes breast cancer.

• Do we really know that, or have we just been told that?

• The frequent negative media reports on breast cancer as well as Black Box warnings preclude women from feeling safe.

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• The fear of breast cancer coupled with the general condemnation of the use of hormone replacement therapy by physician’s posses an insurmountable obstacle against millions of women gaining access to the treatments they need.

• Following the release of the unsettling results of the WHI, millions of women abruptly stopped taking their hormone therapies at the advice of their physicians and on their own.

• This backlash against estrogen therapy resulted in the needless deaths of 42,292 to 48,835 women, according to a recent Yale study.

• Prior to 2002 Premarin was the #1 prescription drug sold in the world.

• Now it is the most likely drug to be discontinued and the least likely drug to be prescribed.

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• Proponents of the Women’s Health Initiative

• The Million Women’s Study

• Data from numerous other studies

• Cancer registries argue that the data is irrefutable

• Hormone Replacement Therapy is associated with a significant increase in the incidence of breast cancer

• They are right if you consider the use of drugs that have hormone-like effects used in these studies the same as rhythmic bio-identical hormone restoration therapy.

• No one seems to talk about this important difference.

• Yet the indictment is of all formulations of hormone replacement therapy without discrimination.

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• Physicians perplexed by the unexpected results of the Women’s Health Initiative were forced to reevaluate the study.

• As a result, many questions about the validity of the findings and soundness of the study were raised.

• HERS Sudy Report. HT can relieve menopausal-type symptoms common in elderly women. ACOG News Release 2002

• Clarke C, Glaser S. (2007) Declines in breast cancer after the WHI: apparent impact of hormonal therapy. Cancer Causes Control; 18(8): 847-52

• Salpeter, SR, Cheng J, Thabane L, Buckley NS, Salpeter EE. (2009) Bayesian met-analysis of hormone therapy and mortality in younger postmenopausal women. Am J Med; 122(11): 1016-1022

• Anderson G, Chlebowski R, Rossouw J, et al. (2006) Prior hormone therapy and breast cancer risk in the women’s health initiative randomized trial of estrogen plus progestin. Maturitas; 55:1-13

• Jernstrom H, Bendahl P, Lidfeldt J, et al. (2003) A prospective study of different types of hormone replacement therapy use and the risk of subsequent breast cancer: The Women’s Health in the Lund Area (WHILA) study (Sweden). Cancer Causes Control; 97:1387-92

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• What insight emerged from the WHI study is that the use of synthetic estrogen and progestin replacement remains questionable at best.

• Numerous experts and research scientists disagree with the conclusions promoted by the Women’s Health Initiative

• Yet these conclusions remain the current standard:

• Medical society position papers

• FDA Black Box warnings

• Therapeutic recommendations are currently derived.

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• The broad interpretation and publicity as a result of the Women’s Health Initiative resulted in a general condemnation of all hormone replacement therapy in postmenopausal women.

• In fact, careful review of the extensive literature suggests that data resulting from the WHI and other recent studies should only be interpreted within the narrow context of the study design.

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Dr. Steven Goldstein, professor of obstetrics and gynecology at New York University stated that

extrapolation from the Women’s Health Initiative (WHI) to other forms of hormone replacement

therapy is unfair and inappropriate.

Dixon BK. ‘Time to move forward’ for HRT. OB.GYN. News. 2006; 41(19):1-3

Turgeon JL, Carr MC, Maki PM, Mendelsohn ME, Wise PM. Complex actions of sex steroids in adipose tissue, the cardiovascular system, and brain: Insights from basic science and clinical studies. Endocrinology Reviews. 2006; 27(6):575-605


• Dr. Leon Speroff, professor of obstetrics and gynecology, and reproductive endocrinology at Oregon Health Science University, Portland, and author of the text book, Clinical Gynecologic Endocrinology and Fertility, said in an interview

• Dixon BK. ‘Time to move forward’ for HRT. OB.GYN. News. 2006; 41(19):1-3

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“The initial negative impact of the Women’s Health Initiative is over, we know the studies

limitations, we know that some of the conclusions promoted in the medial were not correct, and we know that the risks that have

been promoted by the Women’s Health Initiative are incredibly small and perhaps not

real.”


• Failure to take into account the complexities of the female reproductive system has lead to the widespread use of hormone replacement therapies that fail to replicate the normal molecular biology of human estrogen.

• This approach leaves women not only wanting for more, but also fearful of risking breast cancer.

• The reality is that women’s physiology is complex; their endocrine system is as complicated as it gets.

• It becomes critical to the success of any therapeutic treatment that the chemical structure of the hormone (bio-identical), how and when it is given (Rhythmic), the route of administration (never by mouth), and the dosage precisely mimics that of optimal female physiology.

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•Not all estrogens are created equal:

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Estradiol, the principal estrogen in women, interacts through its receptors with

thousands of distinct target genes in the nucleus of cells, with the ability to precisely discriminate function across different cell

types.


• For this reason substitution of a synthetically modified estrogen or the estrogen from another species will not replicate the desired results throughout her system, and can throw a woman’s physiology out of balance

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Survival of the human species over 2 million years implies that estradiol is not a health

hazard. The hormones our bodies make (bio-identical), in both structure and function, have served us well for millions of years.


•A critical amount of estrogen is essential for:

• Normal development

• Shape

• Tone

• Function of the breast

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Logic would dictate that a critical amount of estrogen is essential in maintaining the health of the breast.


• It is only after estrogen levels begin to decline when women enter their thirties do we see the appearance of breast pathology such as:

• Breast pain

• Fibro-adenomatous

• Fibrocystic changes.

• It is only when estrogen becomes deficient do we also see a progressive rise in the rate of breast cancer. 16

Age, not estrogen excess, remains the greatest risk factor for developing breast cancer


• 25 1 in 19,608

• 30 1 in 2,212

• 50 1 in 54

• 85 1 in 9

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Age Risk

Age vs. Risk of Developing Breast Cancer

Eure MA. 2005 Breast cancer risk increases with age. About.comhttp//seniorhealth.about.com/od/cancer/a/br_cancer_age.htm

Kelly, G. F. 1998 Sexuality Today: The Human Perspective. McGraw-Hill Companies


• A female born today assuming current rates stay constant has a 1 in 8 chance of developing breast cancer during the course of her life.

• It is therefore insufficient estrogen levels associated with the aging process that actually places the aging female at higher risk of breast cancer.

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What differentiates a 25-year-old female from a 35 or 55-year-old female is the declining egg count that

reduces her capacity to produce estrogen.


• There is an inverse relationship between estrogen levels and insulin resistance.

• The more estrogen deficient a woman is, no mater the cause, the more a woman develops insulin resistance.

• There is an overwhelming body of evidence indicating a strong association between insulin levels, insulin resistance and risk of breast cancer.

• Insulin is being implicated not only in the etiology of breast cancer, but influences the progression and prognosis of breast cancer.

• Nutritional and lifestyle modifications are clearly indicated to improve insulin sensitivity and are effective tools for reducing breast cancer risk in women.

• Estrogen is a known insulin sensitizer, and an effective agent in also reducing insulin resistance in women.

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http://europepmc.org/abstract/MED/10099938/?whatizit_url_gene_protein=http://www.uniprot.org/uniprot/?query=insulin&sort=score

http://europepmc.org/abstract/MED/10099938/?whatizit_url=http://europepmc.org/search/?page=1&query=%22breast%20cancer%22


• The length of time a woman has been estrogen deficient is a stronger predictor of breast cancer.

• The longer a woman has been in a state of estrogen deficiency the more likely she is to have breast cancer.

• Nearly 70 percent of the participants in the Women’s Health Initiative were between the ages of 60 and 79.

• Hays J, Ockene JK, Brenner RL, et al 2003 Effects of estrogen plus progestin on health-related quality of life. N Engl J Med. 348:1839-1854

• Naftolin F, et al 2004 The Women’s Health Initiative could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition. Fertil Steri 81:1498-1501

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• Most of them had been in a state of estrogen deficiency for decades.

• It takes a breast cancer cell 10 years to become clinically detectable.

• Since most of the cancers were discovered early in the study, one could correctly conclude that the majority of the women in the study who developed breast cancer had previously undiagnosed breast cancer at the time they entered the study.

• The hormones simply uncovered the breast cancer.

• Not a single study to this date has found an increase in hormone users in the earliest stage of breast cancer (noninvasive, in situ disease).

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• If estrogen were carcinogenic, malignancy of the breast would be frequently encountered in pregnancy because the estrogen level rises to great heights (12,000 or greater), especially in the later months.

• Malignancy of the breast is very rare in pregnancy and lactation, only 3 per 10,000 pregnancies.

• Even in the few reported cases, the tumor may well have antedated the pregnancy.

• Childbearing is known to protect against breast cancer, a decrease of 7·0% for each birth a woman has.

• In contrast, the highest demographic for breast cancer are nulliparous (female that has not borne offspring) women.

• It is at high concentrations that estradiol inhibits proliferation and induces apoptosis (programed cell death) of cancer cells.

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• In light of this data, to conclude that hormone replacement therapy is causal to breast cancer defies logic.

• The Women’s Health Initiative is more a study of the impact of aging on a woman’s body rather than the impact of hormone replacement therapy.

• There is a growing body of evidence in the scientific literature that sufficient estrogen is essential for breast health and the reduced risk of breast cancer.

• Not only does estrogen have a primary breast cancer prevention function, but a secondary breast cancer prevention function through its promotion of the hormone progesterone.

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• It is understandable how the notion came to be accepted that estradiol plays a role in breast carcinogenesis.

• Estrogen’s functions are mediated by multiple mechanisms, both genomic through its receptors, and multiple non-genomic (ER-independent) interactions.

• Low levels of estradiol induce powerful signals for cell growth (G1 activation).

• Estrogen levels can be low for 10 to 15 years prior to the climacteric, accounting for the development of PMS and anovulatory menstrual cycles mostly depicted as painful, and heavy.

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• It should be noted that the rise in breast cancer rates corresponds exactly at that time in a woman’s life when her estrogen levels begin to decline.

• Once a woman transitions into menopause her estradiol levels remain relatively low also resulting in a stronger signal of proliferation of breast tissue.

• Conventional hormone replacement practices result in relatively low estrogen, which may account for the rise in breast cancer observed in many studies.

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• During the initial phase of a normal menstrual cycle estrogen levels are low resulting in growth of the endometrium and breast tissue.

• Just prior to ovulation estradiol levels rise in a crescendo spike altering the genomic instructions

• To signal cellular growth inhibition (G1 arrest)

• Induction of apoptosis (programed cell death)

• Promotion of ovulation.

• LaVallee TM, Zhan XH, Herbstritt CJ, Kough EC, Green SJ, Pribluda VS. 2Methoxyestradiol inhibits proliferation and induces apoptosis independently of estrogen receptor and . Cancer Research. 2002; 62:3691-3697α β26

“Interestingly, at high concentrations estradiol inhibits proliferation and induces

apoptosis.”


• Apoptosis is required for normal development and tissue homeostasis.

• The loss of regulation of apoptosis is fundamental to the development of diseases, such as cancer, stroke, heart disease, neurodegenerative disorders, and autoimmune disorders.

• Lewis-Wambi JS, Kim HR, Wambi C, Patel R, Pyle JR, Klein-Szanto AJ, Jordan VC. Buthionine sulfoximine sensitizes antihormone-resistant human breast cancer cells to estrogen-induced apoptosis. Breast Cancer Research. 2008; 10( 6)

• Song RX, Santen RJ. Apoptotic action of estrogen. Apoptosis. 2003 Jan; 8(1):55-60

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“Ironically, high doses of estrogen can induce regression of hormone-

dependent breast cancer in postmenopausal women. Laboratory

studies show that the apoptotic action of estrogen is the major factor leading to cell number decreases in several cell

types. The effects of estrogen are estrogen-receptor dependent.”


• “A team of researchers at CIC bioGUNE has revealed that estrogen can reduce the risk of breast cancer.

• Their work shows that estrogen is capable of reducing the number of breast cancer stem cells, which may explain the lower progression of the tumor and, as a consequence, the possibility of a better prognosis.

• However, nothing or little has been known until now about the effect of estrogen on the tumor-initiating cells.”

• Marie Vivanco, leader of the research team, believes that this study represents a new functional aspect of estrogen do to its capacity for acting in a different way depending on cellular type.

• Estrogen reduces breast cancer stem cells and aggression in breast cancer, study suggests. ( 2011, February 15) Science Daily, Retrieved from

• http://www.sciencedaily.com/releases/2011/02/110214083811.htm

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http://www.sciencedaily.com/releases/2011/02/


• The evidence in favor of estrogen therapy reducing a woman’s risk of breast cancer can be found in the estrogen-progestin arm of the WHI, patients who adhere to treatment throughout the study had a significant reduction in the risk of breast cancer.

• In the estrogen only arm of the WHI, women who adhered to treatment throughout the study had a 33 percent reduction in the risk of breast cancer.

• Dixon BK. ‘Time to move forward’ for HRT. OB.GYN. News. 2006; 41(19):1-3

• A study published in the Journal of the National Cancer Institute, women who received estrogen only therapy for between 10–15 years conferred a 7 percent reduction in risk of breast cancer.

• Ross RK, Paganini-Hill A, Wan PC, Pike MC. 2000 Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin. J Natl Cancer Inst; 92:328–32

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• A study performed at MD Anderson on 309 women with localized breast cancer, there was a significant reduction in the recurrence of breast cancer in the estrogen group.

• Historically, hormone replacement therapy (HRT) is typically avoided for women with a history of breast cancer because of concerns that estrogen will stimulate recurrence.

• A survey on breast cancer survivors in menopause found that women were more concerned about risk of breast cancer recurrence than about risks of osteoporosis, and heart disease.

• Yet breast cancer survivors are interested in treatments that may improve the quality of their life.

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• There is a growing body of new evidence that the use of hormone replacement therapy is associated with a low probability of detrimental effects in early stage breast cancer survivors.

• Several studies observed lower risks of recurrence and mortality in women who’ve used HRT after their breast cancer diagnosis then in women who did not.

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Biglia N, Cozzarella M, Cacciari F, Ponzone R, et al. (2003) Menopause after breast cancer. Maturitas; 45:29-38

Lootta M, Escobar PF. (2011) Hormone replacement after breast cancer: Is it safe? Clinical Obstetrics and Gynecology; 54(1):173-179

Xydakis AM, Sakkas EGR, Mastorakos G. (2006) Hormone replacement therapy in breast cancer survivors. Annals of the New York Academy of Sciences; 1092:349-360

Newcomb PA, Egan KM, Trentham-Dietz A, Titus-Ernstoff L, et al. (2008) Pre- diagnostic use of hormone therapy and mortality after breast cancer. Cancer Epidemiol Biomarkers Prev; 17(4): 864-871

O’Meara ES, Rossing MA, Daling JR, Elmore JG, Barlow WE, Weiss NS. (2001) Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst; 93(10):754-762


• Numerous studies are discussing potential implications for the treatment and control of breast cancer with high dose estrogen as a specific therapeutic agent in postmenopausal women using estrogen mediated processes.

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Lewis-Wambi JS, Kim HR, Wambi C, Patel R, Pyle JR, Klein-Szanto AJ, Jordan VC. Buthionine sulfoximine sensitizes antihormone-resistant human breast cancer cells to estrogen-induced apoptosis. Breast Cancer Research. 2008; 10(6)

Song RX, Santen RJ. Apoptotic action of estrogen. Apoptosis. 2003 Jan; 8(1):55-60

Lewis JS, Meeke K, Ross EA, Kidawi N, Li T, Bell E, Chandel NS, Jordan VC. Intrinsic mechanisms of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation. J NatL Cancer Inst. 2005 Dec 7; 97(23):1746-1759

Lewis-Wambi JS, Jordan VC. Estrogen regulation of apoptosis: how can one hormone stimulates and inhibit? Breast Cancer Res. 2009; 11(3):206


• Estrogen and progesterone (whose production and receptor expression is estrogen dependent) play a critical role at controlling steroid mediated cellular growth regulation in female biology.

• It is the loss of normal growth control that is the hallmark of cancer.

• Speroff L, Glass R, Kase N. Clinical Gynecologic Endocrinology and Fertility. 7th Edition, Lippincott Williamson Wilkins, Baltimore, MD, 2005, Pg. 599

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“Evidence indicates that with increasing duration of exposure, progesterone can limit breast epithelial growth

as it does with endometrial epithelium. Human breast tissue specimens removed after patients were treated

with estradiol and progesterone indicate that progesterone inhibits in vivo estradiol induced

proliferation.”


• In the absence of progesterone, estrogen can induce excessive growth and proliferation of breast tissue.

• When produced in adequate amounts, estradiol promotes the production of growth factors responsible for progesterone receptor expression.

• If there is adequate progesterone receptor expression, progesterone can then slow the growth of breast tissue and promote better differentiation and estrogen receptor down regulation resulting in greater inhibition of growth.

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Therefore, understanding the mechanisms of tissue specific, normal growth regulation and the changes

that occurred during the genesis of cancer may provide insights of both diagnostic and therapeutic

importance.


• There is epidemiological evidence for increased breast cancer incidence in women with a history of progesterone deficiency.

• Premenopausal women found to be progesterone deficient had 5.4 times more premenopausal breast cancer then women with normal progesterone production.

• Interestingly, progesterone deficiency was also associated with 10 times the rate of death from all malignant neoplasms.

• Cowan L, et al. (1981) Breast cancer incidence in women with a history of progesterone deficiency. American J Epidemiol; 114: 209-17

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• Micheli found that the relative risk of breast cancer in premenopausal women was inversely associated with progesterone levels.

• These studies support the importance of adequate progesterone production during the luteal phase and the risk of breast cancer in premenopausal women.

• Since estrogen is directly responsible for progesterone production, this data underscores the importance of adequate estrogen levels in maintaining the health of the breast and prevention of breast cancer.

• Micheli A, et al. (2004) Endogenous sex hormones and subsequent breast cancer in premenopausal women. Int J Cancer; 112: 312-318

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• A compelling area of research is being done on estrogen metabolites and their role in the treatment of breast cancer.

• An estrogen metabolite known as 2-methoxyestradiol (Panzem, an FDA approved drug) is derived from estradiol and works by suppressing tumor growth and blocking the formation of new blood vessels that feed tumors.

• It has the ability to induce cancer cells to self-destruct through the process of apoptosis (programmed cell death), and to destroy blood vessels that feed tumors (anti-angiogenesis).

• In addition to treating sarcoma, lung and brain cancers, 2-methoxyestradiol may be effective in treating breast cancer, in particular the spread of breast cancer.

• LaValle TM, et al. (2002) 2-methoxyestradiol inhibits proliferation and induces apoptosis independently of estrogen receptors α and β. Cancer Research; 62: 3691- 369737


This data underscores the central role of estrogen at

protecting the health of the breast and the need to

understand estrogen’s role not only in the prevention but

also the treatment of breast cancer.

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