The conventional wisdom is that estrogen causes breast cancer. If you want to grow breast cancer cells in a petri dish, you need to add estrogen. And if a postmenopausal woman has an estrogen receptor positive (ER+) tumor you treat it with an aromatase inhibitor, which blocks estrogen production in the breast. So, when researchers looked at what happened to the women in the Women’s Health Initiative study who had had a hysterectomy and who were randomized to get either estrogen or a placebo, the results should have been a slam dunk: increased breast cancer in those on estrogen!

But no! An article published online yesterday in the Lancet Oncology showed that the women in the WHI study who took estrogen alone for about five years had a lower risk of developing breast cancer than the women who were on a placebo. What? Why? In sum it’s complicated.

First a little background. When women enrolled in the WHI, a large randomized placebo-controlled study designed to measure the benefits and risks of menopausal hormone therapy, they were divided into two groups. One group was composed of women who still had their uterus and who would be given estrogen and a progestin or a placebo. The second group was composed of women who no longer had a uterus, and who were given either estrogen alone or a placebo. (The progestin is given to reduce the risk of uterine cancer.)

As you may recall, in July 2002, researchers stopped the part of the WHI study investigating the benefits and risks of estrogen and a progestin after an interim analysis indicated that the risks of this therapy outweighed any benefits it had to offer. But the estrogen-only arm of the study kept going. It wasn’t stopped until 2004, when an interim analysis showed that the women receiving estrogen were more likely to have a stroke than those on the placebo. At that time, the women had been on estrogen for a median of 5.9 years.

When the study was stopped, the researchers asked the women if they would agree to be in a follow-up study, and 7,645 agreed. These women have now been followed for a median of 11.8 years. And as the researchers just reported, what they found took them by surprise. In terms of risk, the women who had taken estrogen were still more likely to have a stroke than those who had been on the placebo. But on the positive side, the women without a family history of breast cancer or benign breast disease also had less breast cancer!

How is this possible, after we’ve had so many studies that have shown that women with higher estrogen levels are at increased risk of developing breast cancer as well as observational studies that showed a higher breast cancer rate in women on estrogen alone? I think that part of the problem is that we’ve oversimplified how estrogen works. We’ve made women think estrogen is always bad. But the reality is that estrogen does not act like gasoline to the fire! In fact, back in the 1980s before we used chemotherapy as much as we do now, metastatic breast cancer was treated with DES, which is an estrogen, and Megace, which is a progestin and both were about as good as tamoxifen.

So, what is the story? The real answer is that we don’t know. One theory is that the cancer cells can adapt to lower levels of estrogen. So, if a woman has been treated for breast cancer by removing estrogen (having her ovaries out, for example) and then has a recurrence, you could then treat her with estrogen, because the cancer cells that had learned to grow when surrounded by low levels of estrogen might be overwhelmed if there were now high levels. In other words, once the cancer cells have adjusted to their environment, we need to make them uncomfortable, and stop growing, by changing up their local environment or neighborhood. This is supported by many doctor’s first-hand experience of seeing a woman whose tumor progresses on a high dose of estrogen stop growing or shrink after the estrogen is stopped.

Another theory is that Premarin, which is the drug the women in the estrogen alone arm of the study received, may itself be a factor. The drug is made from pregnant horse urine, and it contains a variety of estrogens, some of which may act more like tamoxifen and block the receptor. This would mean that we should not assume that bio-identical hormones would offer the same benefit.

Should we give women estrogen alone after menopause to prevent breast cancer? The answer is probably not. For one, this study showed that the decrease in cancers only occurred in the women who were at low risk of developing breast cancer to begin with. And for those who are high risk, tamoxifen and raloxifene are better choices.

However, it does mean that if you are not at high risk for breast cancer, have had a hysterectomy, and are looking to relieve some of your menopausal symptoms, you can use estrogen alone for up to five years knowing that it won’t increase your breast cancer risk. (Still, don’t forget that the estrogen alone study was found to increase the risk of stroke.)

Finally, all of us doctors, scientists, and women need to come to terms with the fact that the relationship between estrogen, menopause, and breast cancer is far from simple. Like all relationships . . . it’s complicated!

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26 Responses to Estrogen and Breast Cancer: It’s Complicated!

  1. Jonathan says:

    Thank goodness for Dr. Love and the voices of reason! I agree wholeheartedly with everything expressed here. What’s worrisome, though, is that women might be told by their doctors that, if they’ve had a hysterectomy, it’s okay to use estrogen only for longer than the 5-7 years of the WHI. What’s more, as Dr. Love pointed out, these findings may be construed to mean that ANY type of estrogen reduces breast cancer. It is very possible that estradiol may in fact be more dangerous than Premarin, which contains several different estrogens that are not natural to women. So there is the chance that Premarin is weaker than estradiol and therefore causes either a washout effect by blocking a woman’s natural estrogen or directly kills cancer cells in women with hysterectomy through a “binge” effect. People forget too that hysterectomy causes a lower-estrogen environment that cancer cells may have adapted to if they managed to survive the “starvation”. Estradiol alone has been shown to increase breast density more than Premarin. Also, the French E3N Study showed estradiol without progestin or progesterone raised breast cancer risk after only 8 years of use, whereas the Nurses Health Study suggests it takes 15-20 years for Premarin to raise breast cancer risk. So the new findings should not be taken to mean that estrogen, categorically, lowers breast cancer risk.

    Despite these intriguing data, I hope the pro-estrogen zealots don’t flat out ignore that the hormone by itself does pose serious risks, namely stroke, blood clots, abdominal aortic anuerysm and dementia (all according to the WHI). So this therapy is not safe to use over the long term, regardless of its effects on breast cancer.

  2. Diane Manley says:

    My cancer was stage zero, DCIS. I had a positive estrogen receptor. After 18 years of biopsies, I requested a bilateral mastectomy with recontruction. I take Evista but don’t understand why. I have had a hystrectomy and I have no breast tissue and I am 67 years old. Does this make sense?

  3. Lois says:

    I keep hoping that some of the breast cancer $ will be put toward endowing some kind of training program specifically to provide endocrinologists who specialize in cancer, so that each of us would actually be seen and evaluated and counseled and have documented recommendations made by an endocrine specialist very early on as part of our treatment process, instead of all this stumbling around in the dark.

  4. Sharon says:

    There times that even if you take a blocker, it may not do it’s job I took it for 5 years after having Breast Cancer and still got Breast Cancer on the other breast.

    This may not be true for some women.

  5. Susan Love says:

    @ Jonathan…thanks we are in total agreement
    @ Diane The Evista is probably for your bones, but if you have questions ask your doctor
    @ Lois I completely agree….It is amazing how much we still don’t know
    @ Sharon You are right. These drugs reduce the chances that you will get a recurrence or another breast cancer but do not eliminate it.

  6. Teresa Masters says:

    Today, 3/14/12, after my lumpectomy of 10/11/11, I requested return to HRT. Mammography failed to ever see my cancer, HRT kept me vital, strong, active. My quality of life choice is to return to HRT. I am in tact, 80, and was in the WHI control group. I felt the whole estrogen fear was overstated, poorly conducted, and yes, I was asked that if I were to continue, I keep them appraised. I was on HRT for close to 30 years.

  7. Eileen Montgomery says:

    I think the whole estrogen thing is just grabbing for anything, estrogen has been around, since Eve, bc has rapidly climbing for the last 30 years.

  8. I am 81 — lumpectomy 3 yrs ago — hysterectomy 37 yrs ago — tamoxifen has
    given me hot flashes — oncologist has
    prescribed Melatonin and it has worked!!!
    Do you have any comments, concerns??

  9. Janis Cicero says:

    I had a lumpectomy (atypical hyperplasia) almost 20 years ago. At that time I was asked to participate in the study that Dr. Bernard Fisher was conducting, which would entail taking Tamoxifen. I declined. I was forty two. Ten years later my mother, seventy-nine, had DCIS, a radical mastectomy. Due to all this, I have never taken estrogen, although it would certainly make certain issues in life much easier. I’ve had several doctors over the years recommend it, but since the pendulum continues to swing back and forth,I’ve never felt confident enough to do so. What’s your opinion, Dr. love?

  10. Debra says:

    Does this mean that I, so far a 3 and 1/2 yea rbi survivor who was treated with lumpectomy and radiation for Stage 1 ER sensitive BC, can take Estrace? My doc was so upset that I did so that she switched me from Arimidex to Tamoxifan after 3 years.

    I no longer take the Estrace but I no longer have sex. Quite a compromise at age 63.

  11. Sandi B says:

    Good information, yet the verdict still remains out. I am a BRCA 1 carrier with a strong family history of breast, ovarian and pancreatic cancer. I had a complete hysterectomy at 45, bilateral prophalactic mastecomy at 50 and have been using estradiolpatches for 7 years now (currently 52 years old). The estrogen patch greatly relieves the side effects of the hysterectomy and has given me a great quality of life. Without breast tissue to worry about, I wonder how much longer I can safely remain on the estrogen patches? Sounds like stroke is now my #1 concern.

  12. anne vincent says:

    Prior to the WHI study there were numerous studies, over many years, that failed to demonstrate an increased incidence of breast cancer in women utilizing unopposed estrogen. There has been concern about Provera, among many Gyn./Endocrine experts for a long time…and that was the progesterone utilized in the WHI study. Perhaps it would be reasonable to repeat the WHI study using a non-synthetic progestin. Perhaps it would also be more reasonable to study intraductal breast cells exposed to combinations of various androgens/progestins/estrogens to determine which specific combinations stimulate which cell characteristics. I suspect this has been done… and also suspect that the multitude of other confounding factors (genes, infections, toxins,etc.)keep the precise causes of this epidemic obscured.

  13. gretchen says:

    I have been taking premmarin for over 30years.
    Had a hysterectomy over 30 years ago. Have cystic breast and just started having yellow nipple discharge from right breast. After sonograms and MRI nothing. The impressions “no interval development suspicious enhance in either breast. However, further evaluation & mgmt. of nipple discharge should be clinically determined” What does that mean. anyway my BI-RADS 2: Benign findings

  14. 12/99 had surgery for DCIS. Pathology came back with 3mm invasive component. Went back in for full node dissection, 22 neg. nodes. Had 6 wks radiation, 5 years tamoxifen and 2 hrs femara (stopped femara due to high cholesterol). Just went for 12 year check up. Found DCIS in other breast, path report not back yet. Looking at 6 weeks radiation. If contained in the cut, do you do tamoxifen a second time or inhibitors. This biopsy ER PR positive HER2 neg (same as last time) only difference now intermediate grade, last time high.

  15. melodie says:

    2010 stage 1 er positive and dcis. treatments have been lump/rad/tamoxifen/lupron.
    2012 dcis other breast.. would you suggest same treatment for this breast?
    i feel i have aged 10 plus years thru all of this.

  16. The UK MWS found estrogen use increased breast cancer risks. The WHI study underestimates risks due to lack of genuine never takers. A majority of women randomized to HRT or placebo had previously taken OCs or HRT and other swopped during the study.

  17. Mary Young says:

    14 years ago I was diagnosed with DCIS, had a mastectomy. Then 10 years later had a recurrence in the same breast, which is now stage 4 in the bones. First in the sternum and now in the spine. I was first put on femara for 3and half years and until it failed and now just started faslodex. I had gone for a second opinion at Duke and the Dr. their recommended that I go on estrogen. I didn’t feel comfortable with that and tried to research it as much as I could and really could not find much good information on it. I’ve only been on my new med’s 6 weeks so don’t know how it is going to work out yet hoping for the best.

  18. Mary M. says:

    Family history of BC, dense breasts and several biopsies had bilateral reduction and removal suspicious tissue By Dr.Love @BI in Boston then in 40’s had hysterectomy &bilatoophorectomy at 67 diag. with 12 neg. nodes invasive ducal ca. Grade 2/3 no evidence of metastatic ca. Oncotyping score of 17 on Arimidex-severe side effects. Would like to stop it. Also planning on having the other breast removed. What are your thoughts.

  19. Dottie Gross says:

    Had a hysterectomy 27 years ago. Have been on Premarin every day for 22 years and cut back to .2mg twice a weeks which keeps my systems at bay. I have spoken to my GYN and together made the decision that considering the quality of life I was told this small does of the Premarin should be ok.
    Nine years ago I did have a breast biopsy which came back no malignancy but abnormal cells and an overabudance of cells. Everything has been fine since.

  20. Marcia Campbell says:

    Diagnosed 10 years ago with ER+ in right breast, had lumpectomy, chemo, radiation. Was on tamoxifen for 2-3 years then switched to Femara and have been on it ever since. My oncologist said he wanted me on it for 10 years. I want to stop taking it due to the hot flashes, hair loss, no libido, very dry skin and looking and feeling like I am 20 years older than my 51 years. I was also Her2+. Mom had breast cancer at age 75. I have two daughters in their twenties. My mammos have been negative. What should I do?

  21. Susan Griggs says:

    Adopted, calcification biopsy came back ADH having lumpectomy next month and last ovary removed at same time ( had cervix , uterus right ovary & endometriosis out two years ago) . I am having ovary out in lieu of being on Tamoxifen.

  22. v says:

    I had a double mastectomy after slightly invasive BC that began in my milk ducts… (my breasts were small and a lumpectomy would have taken most of breast)… I also have/had estrogen positive receptors, so have been told to avoid estrogen for my hot flashes… but if my breasts are gone… why avoid estrogen????

  23. jean123 says:

    Had a lumpectomy 3mm triple neg…surgeon suggests Radiation. I don’t want to do….fromwhat I am reading if it does come back it doesn’t come back in the breast…so why do radiation. Also want to start Bioidentical hormone replacement…any risks in doing that?

  24. I had a complete hysterectomy 1980 at the age of 34. I have suffered with symptoms all these years. I had a Heart Attack 3 years ago I am thinking of trying hormone to find some quality of life.

  25. DOLORES RIVAIT says:

    Im 81 years old, took estrogen since I was in my 50. Have no ovaries or uterus. I just had a lumpectomy for stage ! breast cancer. And will need 16 treatments of radiation plus tamoxifen. I have refused the TAMOXIFEN. what are my chance for cancer returning in the future. I hope IM making the wright choice.

  26. SuD says:

    My sister had a hysterectomy in 2001. It was an elective surgery for her, since she had many beningn lumps in her uterus. She was 43 years old. The doctor told her to wait, the lumps would shrink after menopause anyway, but she decided to have it done. Six years later she found a lump in her left breast. It was ER+ breast cancer in situ. Lumpectomy followed with radiation and tamoxifen for five years. No cancer at check ups… Then exactly at the fifth year checkup they found some cancer cells in her lymph nodes. Chemo plus surgery… Year later spine mets, radiation followed, cancer was killed, but showed up a year later in her liver, left breast, colon, but by then it changed into a triple negative kind of cancer. She is on docletaxel that is awful, but seems like keeping the mets at bay for now.
    My sister-in-law had some lesions on her cervix, that was precancerous. After trying to treat it, it came back, so her doctor decided to have a hysterectomy in 2002. About five years later she was diagnosed with breast cancer. I lost touch with her, so I don’t know any details of her condition. In both cases the doctors left the ovaries.
    Would this be a coincidence that after hysterectomy breast cancer shows up?
    Has anybody studied corelation between the two before?

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