Hearing about estrogen replacement, many women unconsciously cover their breasts with their arms. The word “estrogen” makes them think of the “enemy”— breast cancer. Scientists and doctors often feel the same way. This is understandable as a large body of data supports the widely recognized ways that estrogen can “fuel the fire” of estrogen-positive breast cancer cells.

But it’s not the whole and accurate estrogen story.

A shifting paradigm about the complex terrain of estrogens is showing that sometimes estrogens can prevent breast cancer, and sometimes even help treat breast cancer.
Did you know estrogen has been used to treat breast cancer? The use of high-dose estrogen was the first successful breast cancer therapy, which began in the 1940s. Using oral estrogens to treat breast cancer continued all the way into the late 1970s until Tamoxifen (an anti-estrogen) was introduced. When Tamoxifen became the standard of care, estrogen therapy pretty much stopped.

The most powerful synthetic and pharmaceutical estrogen ever invented, DES (diethylstilbestrol), which is 50 times more powerful than the natural estrogen a women’s body normally makes, was the preferred method of treating metastatic breast cancer in the 1960s and 1970s. Metastatic cancer is when cancer cells have spread from the initial primary tumor out into other parts of the body. This is diagnosed as a stage 4 cancer and is life threatening. DES was so effective it was described as making tumors melt away in 30% of women treated with it. (More on the DES story downstream in this blog.)

If estrogen was used to treat breast cancer decades ago, why is estrogen now regarded as causing breast cancer? Or looked at with much more apprehension? The Women’s Heath Initiative. This is the research that first created fear about estrogen but ultimately proved estrogen’s breast protective personality. It’s quite a tale all female breast owners should know.

For many decades women had been prescribed estrogen therapies to prevent diverse ailments of aging, from heart disease to bone loss, from aging skin to frailty. But there had never actually been a randomized controlled study (the holy grail of research) proving these benefits. To finally verify the benefits of estrogen replacement, many prestigious institutions came together to initiate the first randomized trial on hormone therapies. Most all the scientists involved thought the studies would prove what women and doctors had experienced for years, that estrogen replacement worked miracles.

These hormone trials were part of a large collective research effort called the Women’s Health Initiative (WHI). The WHI was a huge number of studies looking at how women age and how to protect them. Maturing women are our largest and fastest growing demographic, so science and our government wanted to know how to keep women well without bankrupting Medicare.

The WHI looked at many aspects of health and aging, from intimacy to bone treatments to diet to hormones. The studies looking at hormone replacement effects had two groups of women, referred to as arms. These arms were examining “if” hormone replacement prevented disease and slowed down aging.

At that time in the US, the most commonly used estrogen therapy, called Premarin, and was manufactured from horse’s urine. When combined with a synthetic patentable (can own, market and make money from it) version of progesterone (medroxyprogeserone), the combo product was called Prempro. These were the hormones used in the WHI. They were not exact (bioidentical) replicas of what a woman’s body naturally makes.

By the way, since use of these synthetic hormones has nosedived, the CEOs from these older companies are now in phase 3 trials rushing to introduce their own bioidentical hormones to the public (called Replenish).

In the WHI, the women in the estrogen-only arm were given Premarin and in the combination-arm they received Prempro. Both groups were compared to women receiving placebo.

Decade of estrogen fear.

The hormone studies of the WHI were prematurely stopped in July of 2002. Initial reports suggested that giving hormone therapies to women were causing some of the very issues that replacement was intended to prevent, such as heart disease and blood clots, and breast cancer.

Shock rippled across the U.S.

Doctors en mass stopped recommending hormone replacement. Of note is that in Europe, most gynecologists recommend natural estrogens (identical to what women’s bodies naturally produce). Since these initial WHI negative results were secondary to the use of non-bioidentical hormones, less European doctors stopped prescribing hormone therapies.
But in the U.S., women became fearful of estrogens. And so did their docs. This created the “decade of estrogen fear” that unfortunately still lingers in the minds of many women and physicians today.

Re-analyses. The results of the WHI were so shocking and counter-intuitive to the results that millions of women (and the physicians treating them) had clinically experienced that a flurry of “re-analyses” began. Scientists started to take a deeper dive into what the WHI statistics were actually telling us. These re-analyses were run at prestigious labs all across the country. They wanted to understand if the data could withstand closer scrutiny and if the growing fears were warranted.

One such analysis of the WHI was presented by Joseph Ragaz M.D., a researcher from the University of British Columbia, at the San Antonio Breast Cancer Symposium in December, 2009.  Dr. Ragaz’s research found something shocking. The women in the estrogen-only arm, without the synthetic progestin, had a significant decreased risk of getting breast cancer. The women on estrogen replacement by itself had a reduction of breast cancer incidence by 32%.

This re-analysis gave a very different perspective on estrogen; that in certain circumstances, estrogen protected breasts against breast cancer. Dr. Ragaz stated that the findings were strong enough to actually refer to estrogen as a chemo-preventive (cancer protective) agent and that further research was warranted.

More re-analyses emerged. One article, in the April 6, 2009 issue of JAMA (Journal of the American Medical Association), found that women who had been on estrogen replacement for six years, but followed for eleven years, had a 23% lower risk for invasive breast cancer compared to women who had been given placebo. Another article was published in JAMA in 2011, finding this same continued protective effect. Andrea La Croix, Ph.D., a scientist from the Fred Hutchinson Cancer Research Center in Seattle, commented on this phenomena. Dr. La Croix said this persistent protective effect of estrogen on breast tissue was unexpected but statistically solid.

So, the initial blush of warnings from the WHI hormone trials suggested hormone therapy might cause breast cancer, but with more in-depth investigations over time, the opposite was emerging. It seemed that the group of women that did experience a higher risk of breast cancer, were on the combination therapy. An accusing finger was pointed at the synthetic progestins, but not at the estrogens (nor at the bioidentical progesterone that functional medical practitioners have women protectively take with estrogens).

A variety of scientists like Dr. LaCroix started to refer to the WHI as the first randomized trial to give evidence that if you give healthy women estrogen therapy within 10-years from the initiation of their menopause, or to post-menopausal women without a uterus, this reduced the risk of getting breast cancer.

Two other movers and shakers agreed. Dr. Craig Jordan, the estrogen and cancer scientist who invented Tamoxifen, and Leslie Ford M.D., associate director for clinic research at the National Cancer Institute’s Division of Cancer Prevention, wrote an article called the Paradoxical Effect of Estrogen on Breast Cancer Risk. This research showed that sometimes estrogens actually not only prevent breast cancer, they cause breast cancer cells to die (cell death is called apoptosis). The ability of estrogen to do this seems to be activated by a period of lack of estrogen exposure (menopause or anti-estrogen therapy) and then re-exposure to estrogen. The absence of estrogen and then re-exposure retriggers breast cancer cells to die, in some women. Cell populations emerge with a vulnerability

The father of gynecology. Dr. Leon Speroff is a gynecologic icon. Dr. Speroff co-authored the book that trains female doctors, titled Clinical Gynecologic Endocrinology and Infertility. Dr. Speroff was aware of the bad press estrogen had been getting, but he was also aware of its benefits. Dr. Speroff began to publish a flurry of professional articles criticizing hormone replacement being withheld from women, and encouraged doctors to keep testing, prescribing and monitoring.

Dr. Speroff reminded us that doctors had been using estrogen therapy for many decades and getting stellar results. He emphasized that these years of doctor experience should not be trumped by one study that now seemed so flawed. Dr. Speroff reminded the profession that fear sells. When re-analyses data emerged, it wasn’t fearful and didn’t make headline news. I spent three years writing Safe Hormones, Smart Women (Awakened Medicine Press, 2010) to let the public in on these controversies and realities.

Dr. JoAnn Manson, one of the lead researchers on the WHI, the very same study that first got doctors to stop prescribing estrogen, has come round to looking at estrogen in a new and improved way. Dr. Manson said the breast protective effects seen in the estrogen-only arm in the WHI is probably due to estrogen’s alter ego ability to act like Tamoxifen. But Tamoxifen is an anti-estrogen. How can an estrogen act like an anti-estrogen? Oy veh.

DES more in-depth.

To answer this question, we have to go back to DES. DES (diethylstilbestrol) was a drug given to multiple millions of pregnant women for 36 years. It was outlawed in 1971 when it was finally proven to be the most powerful endocrine-disrupting and cancer-causing drug even invented. Sir Charles Dodds, the same doctor and scientist who invented plastics (which are also estrogenic), created it. DES is now labeled a class-1 carcinogen. It’s never to be used during pregnancy. But it was used for years to treat breast cancer. How can that be? The original studies showed it shrank tumors in many women with breast cancer. But the longer term follow-up studies were really mind-bending.

The Mayo Clinic ran a follow-up analysis of one of its older studies comparing DES treatment to Tamoxifen treatment on breast cancer patients. This follow-up study showed that some breast cancer patients treated with DES actually lived longer compared to some breast cancer patients treated with Tamoxifen. How? The Mayo Clinic researchers were able to show that estrogens, given at the right time, can deliver signals to breast cancer cells to instruct them to ”die.” This is what Dr. Jordan had been talking about.

Sometimes robust estrogens, like DES, can make breast cancer cells that were not responsive to drugs like Tamoxifen, start to respond. A Norwegian study published in 2001 showed that half of 32 breast cancer patients who had become resistant to Tamoxifen or other endocrine therapies, once treated with high-dose DES, then became responsive to the endocrine therapies. This meant that a woman who had become non-responsive to Tamoxifen or an anti-aromatase inhibitor could be rebooted to once again respond to them by the use of a powerful estrogen. The natural next question was: could a woman’s own home-grown estrogen be protective, like DES, too?

The answer was yes. Matthew Ellis, M.D., Ph.D., director of the breast cancer program at Washington University in St. Louis, answered this question and published his results. Dr. Ellis showed that giving both high dose natural estrogen (30 mg/day) or low dose estrogen (6 mg/day) to women with metastatic breast cancer, who had failed aromatase inhibitors, then helped effectively kill breast cancer cells. These women were given oral estradiol, identical to the active form of estrogen inside a women’s body. The estradiol shrank tumors in 30% of the women. The adverse side effects from the estrogen therapy, especially the lower dose, were less toxic than from chemo, and certainly less costly.

So research is showing that estrogens help prevent breast cancer in some women, help eradicate breast cancer cells that are sleeping, and help some women become responsive once again to breast cancer therapy that had stopped helping them.
Dr. Craig Jordan commented on this rebooting of response to endocrine therapies by estrogen: “After five years of anti-estrogen therapy, a switch takes place inside breast cancer cells which makes them resistant to these anti-estrogen agents. When estrogen is then used, it triggers breast cancer cell death, not growth.”

The good estrogen dominance. There are over 60 estrogen-acting molecules inside the human body. Some signal growth and that is what many cancer doctors are, of course, concerned about. But some signal controlled growth, like estrogen receptor beta signals. These signals keep us from getting primary cancers and from recurrences. Specific types of estrogens, herbs, and foods turn on these protective estrogen signals. Thus, estrogen receptor beta is the “good estrogen dominance,” yet is not widely known. This is another way estrogen is easily misunderstand. Too often women hear about the bad estrogen dominance and inappropriately start to think of all estrogens as bad.

My story is about how estrogens are complex. I am a DES daughter, meaning my mother was given DES while pregnant with me. Exposure to DES in the womb is a serious and dangerous situation. Many DES daughters cannot have children, go on to suffer multiple cancers, like breast and kidney, and have ongoing issues from insulin resistance to premature death.

I had breast cancer 21 years ago. Many DES daughters get breast cancer around the same age. This has been verified by meticulous research from Dartmouth. I had a very rare type of breast cancer. It had not ever been diagnosed in any woman in the U.S. before me. Yet all my doctors said I should definitely take Tamoxifen. I pondered if that was right for me. After all, my case was so unusual. I was a DES daughter and now I had a rare type of breast cancer that none of these doctors had ever seen before. How did they know if Tamoxifen was right for me?

I am someone who takes matters into my own hands. I sleuthed and discovered that Dr. Jordan was the inventor of Tamoxifen. Dr. Jordan had a lab at the University of Michigan, my alma mater. So I called him up. What the heck. By this time I was a hormone scholar at an estrogen think tank at Tulane University. He answered. Yikes. I told Dr. Jordan (who insisted I call him Craig) about my situation. I asked what he thought I should do. To his credit, Dr. Jordan said that no one had ever asked him about taking Tamoxifen in a DES son or daughter before. Craig promised he would get back to his drawing board, research it, and give me a ring.

Good to his word, Dr. Jordan kindly called back in a week. Craig said that the DES and Tamoxifen molecules were so similar, he felt they were too similar. Dr. Jordan said, “If it were me, I wouldn’t take it. So I didn’t.

When I told my doctors I wouldn’t take it and why, they called Dr. Jordan and me such bad names I wouldn’t repeat them here in print. But this information came directly from the horse’s mouth. And wasn’t it doctors who prescribed the DES for my pregnant mother in the first place? I had gotten the memo, back in the womb, that we have to take charge of our own health. My life has shown me that no one will ever take your health as seriously as you will. Or see the bigger picture as you might. But it take a lot of due diligence. And balls.
It’s been 21 years since I was diagnosed with breast cancer. Sometimes I go to a new doctor who reads my files and shakes his or her head, telling me in no uncertain terms that I made a huge mistake not taking Tamoxifen. When I tell them about Dr. Jordan and the story, and here I am safe 21 years out, I still get the deer-in-the-headlights look. Many of today’s young doctors might not have ever heard of DES.

Estrogen is complex. She’s misunderstood. She is protective in many ways.

When you ask a practitioner if you are a candidate for estrogen and other hormonal therapies, you are more apt to get a misinformed answer than a right one. Most doctors stopped using estrogens back in 2002 and are just starting to put their toe back into the hormone replacement waters.

I had the honor to interview the past president of the North American Menopause Society, Dr. Stephen Goldstein. I asked Dr. Goldstein his opinion on estrogen replacement. He said that it was a huge shame that millions of women got the “fear memo,” but not the “new memo” that estrogen protects breasts more than harms them. Of course, it’s a complex issue of all the estrogens in relation to each other, in ratio to other hormones, in cross-talk with gut and nutritional health, and personalized to the individual woman. But on the whole, hormone replacement therapy given to the right woman, at the best time, in a tested and monitored manner, can be protective for years to come. You can read that interview here.

I discuss the Women’s Health Initiative study in easy-to-understand details in Safe Hormones, Smart Women (available on Amazon and at DrLindseyBerkson.com), how to take safe and strategic actions to keep you well, and the intimate role of nutrients, hormones and the gut.

Knowledge is power.

It’s too easy and too common to get wrong answers when questioning any health provider about hormone therapies. Stay informed!

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Endnotes
Br Med J 1944;2:393-8. Influence of Synthetic Oestrogens on Advanced Malignant Breast Disease, Haddow A, Watkinson JM, et. al.
JAMA. 2009 Aug 19; 302(7): 774–780.
Lower-dose (6 mg Daily) versus High-dose (30 mg Daily) Oral Estradiol Therapy of Hormone-receptor-positive, Aromatase-inhibitor-resistant Advanced Breast Cancer: A Randomized Phase 2 Study Matthew J, Ellis MB et. al.
JAMA 2011;305:1305-14, Health outcomes after stopping conjugated equine estrogen among menopausal women with prior hysterectomies: a randomized controlled trial. La Croix AZ, Chebowski RT, et. al.

Maturitas. 2015 May;81(1):28-35 17β-Estradiol and natural progesterone for menopausal hormone therapy: REPLENISH phase 3 study design of a combination capsule and evidence review. Mirkin S, Amadio JM et al.

Cancer Prev Res 4(5); 633–7. Paradoxical clinical effect of estrogen on breast cancer risk: a “new” biology of estrogen-induced apoptosis. Jordan VC, Ford LG.

J Natl Cancer Inst. 2011 Jun 22;103(12):920-1. Estrogen’s dual nature? Studies highlight effects on breast cancer. Twombly R.