Saturday, March 5, 2016

Are High Levels of Estrogen Dangerous?

It is interesting that high dose estrogen was the first effective treatment of choice for metastatic breast cancer through the mid to late 1970's. That is until Tamoxifen was introduced and replaced estrogen therapy due to its superior toxicity profile. Tamoxifen and raloxifene belong to a class of anti-estrogen drugs called SERMs. According to James Ingle, Professor of Oncology and Foust Professor in Mayo Clinic College of Medicine, there are genetic markers that appear to be associated with response to SERM treatment. The same genes are involved in regulation of the BRCA genes, and so may also be important in selecting patients for PARP inhibitor therapy, a therapy that is currently in clinical trials for BRCA-related and triple negative breast cancer.

The story of estrogen's role in breast cancer is starting to look like Dr. Jekyll and Mr. Hyde. A spate of recent studies demonstrates that the hormone—long known to fuel growth of most breast tumors—may actually be effective in treating breast cancer, or even preventing it.

Using estrogen to treat breast cancer is not new—high dose synthetic estrogen DES (diethylstilbestrol) was a mainstay in treatment of metastatic breast cancer in the 1960s and 1970s. But new research has shown that even lower doses of human estrogen (estradiol) has a therapeutic benefit. Furthermore, in the laboratory, scientists are now demonstrating that estrogen can kill breast cancer cells, causing apoptotic death.

Len Lichtenfeld, M.D., deputy chief medical office at the national office of the American Cancer Society in Washington D.C., is familiar with estrogen's dual nature in treating breast cancer. “In the 1970s, I got responses by putting advanced breast cancer patients on high-dose estrogen, and sometimes, by taking them off of it,” he said. “We now think that worked by changing the hormonal environment, and there is not anything wrong with looking at use of estrogen again.”

Two years ago, Matthew Ellis, M.D., Ph.D., director of the breast cancer program at Washington University in St. Louis, published a key study in JAMA on the treatment of breast cancer using oral estradiol, identical to the principal active form of estrogen in a women's body. Ellis found that low-dosage estradiol (6 milligrams), a level similar to that found in premenopausal women, was as effective as 30-milligram dosages, the amount found in pregnant women. Tumors shrank or stopped growing in about 30% of women in both investigational groups, but toxicity was reduced in the low-dose group.

Some of the cancers recurred, but about a third of those women then responded again to the anti-estrogenic aromatase inhibitors. That meant that patients who had previously taken aromatase inhibitors but had become resistant to them experienced tumor shrinkage using estradiol—a treatment that costs $1 a day. Later, after they became resistant to estrogen, they responded to anti-estrogens again, said Ellis. These treatments were much better tolerated than chemotherapy would have been, Ellis said, adding, “This strategy is very effective in a select group of patients.”

Jordan has focused his Georgetown lab on understanding how estrogen kills breast cancer cells that have become resistant to the anti-estrogenic effects of tamoxifen, raloxifene, and aromatase inhibitors.

“After five years of anti-estrogen therapy, a switch takes place inside breast cancer cells and resistance to these agents develops,” he said. “Now when you use estrogen, it triggers [cancer cell] death and not growth.” Jordan adds that if researchers can find the mechanism that pulls this trigger, it may be possible to come up with a new, targeted therapy that mimics estrogen in its Dr. Jekyll guise.
JNCI J Natl Cancer Inst (2011) 103 (12): 920-921.
doi: 10.1093/jnci/djr233

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hormone replacement therapy, hormone imbalance, women to women, bodylogicmd, hormone replacement after hysterectomy, bioidentical hormones, HRT, women's health, men's health, TS Wiley, The Wiley Protocol


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