December 10, 1997
"The Yin and Yang of Estrogens and Antiestrogens"

The topic is so titled because this is what estrogens and antiestrogens really are: complex biological compounds that can have complex opposing effects. There is much uncertainty in clinical medicine as to how to use these hormones appropriately,i.e. when they might be helpful or harmful. Issues can be clinical, psychological, emotional, timely, such as prevention benefits.

Comments and Questions:

Dr. Tripathy first introduced a guest, Dr. Keith Block, a physician visiting from Illinois, who has done a lot of work in integrative medicine, who will participate in tonight's Forum.

Dr. Tripathy wanted to know the impression of the group about using HRT after early stage breast cancer. The impressions were all negative. Dr. Tripathy then asked about the impressions of HRT in general. He stated that there are no easy answers, many pros and cons. Steroid hormones have a negative connotation for some, but a positive connotation for others. It can be seen as a natural replacement, something which is associated with health and youth, slowing down the aging process. The human body was probably designed to have estrogen for life, as women in gereral didn't live past menopause. Now that we are living longer we need to study the effects of withdrawal of estrogen.Studies that have been done have looked at very focused endpoints: definite benefits in regard to osteoporosis and heart disease, but are less clear when it comes to aging of the skin and Alzheimer's disease. From a public health standpoint it is positive to take HRT, even with the approximate 10% increase in risk of getting breast cancer, although here it is necessary to look at subgroups, as the risk on women with a history of breast cancer may be significantly higher.

Designer Estrogens. The subject of designer estrogens was introduced. The second estrogen receptor was discovered this year. Estrogen binds to the estrogen receptor and has a complex effect on cells. This effect is different on different cells in the body. Therefore the effects of estrogen are tissue specific: every tissue behaves differently when exposed to estrogen. Tamoxifen is a yin/yang drug. In some tissues it's effects are proestrogenic and in some antiestrogenic. In most cells the effect of tamoxifen is antiestrogenic, but in the uterus, the bone and the liver it's effect is proestrogenic. This may be different in younger women who are premenopausal.

This now gives us the opportunity to tailor make drugs with the ideal properties of estrogens and antiestrogens.

Roloxafene (Eli Lilly) is a drug which, like tamoxifen, is a selective estrogen receptor modulator (SERM). Like estrogen it has a positive effect, lowering the rate of osteoporosis and heart disease without stimulating breast and uterine cells. In early trials it has been found that roloxafene does not stimulate uterine cells as tamoxifen does. Other positive findings include: lower lipids, improved bone mineral density, although there has been no reduction in heart disease, the results are trending in the right direction. There has also been 80% fewer breast cancers to date than in the placebo group.Very promising so far in trials.The side effect profile, however, is no better, patients still get hot flashes and mood swings. Other SERMS are in trials right now.

As we are not sure if the drug performs in the adjuvant setting, Dr. Tripathy is not currently switching patients from tamoxifen. He would like to see a randomized trial comparing roloxafene to tamoxifen.

Phytoestrogens. Estrogens from natural sources like plants (but note that chemicals like DDT can have the same chemical structure). These actually mimic the effect of estrogen in the body. Small amount of these estrogens can actually be a cancer preventative, whereas in larger doses they can cause cancer. Dr. Tripathy thinks that it is important to look at the effects of diet on cancer therapy. In many parts of the world the use of soy and flavinoids can be shown to affect estrogen pathways. People who have diets high in soy also tend to consume less alcohol and have better access to healthcare (at least in this country). Because of all of these variables it is hard to prove the effect of diet, but we can assume that a more primitive diet (lower on the food chain) is to be preferred to a high fat diet. Estrogen is known to be stored in the fat cells. Dr. Tripathy said that although a soy based diet is beneficial, megadoses of supplemental extracts can have a deleterious effect. Progesterone derived from yam extracts can be good, but taking progesterone doesn't raise estrogen levels, even though it could be considered a precursor to estrogen. Positive effects of progesterone taken at low doses include eleviation of hot flashes.

In summary, the message is a matter of degree. Any dietary change that is moderate will most likely be beneficial, but you can certainly overdo with extracts, etc. (including yam extract). Dr. Block says you can eat soy in abundance, but you should be aware of the multiphasic effect of these food sources.

Tamoxifen Therapy. Five years of therapy seems to be optimal, no increased benefit between 5 and 10 years. With women 50 and over there is no difference between 2 and 5 years of therapy. With women under 50 there is a difference. Taking a holistic view, balancing the body, diet and therapies seems to be the best approach. Dr. Tripathy feels that the problem is that there are no good surrogate markers to test the value of other therapies without doing large studies. Tissue sensitivity tests which expose tumors to different chemotherapies can tell you what drugs not to use, but not what drugs to use. Use of cells cultured from tissue samples to look for markers need to be looked at. The question was asked, "How can you know if your receptor status has changed if you are on tamixofen for 5 years?" In general, tamoxifen is the right thing to do, even if 30% of the time (in the lab) you have lost your ER status.

Tamoxifen Studies Reviewed:

1. NSABP study compared tamoxifen with no therapy for 5 years, then those patients were re-randomized for another 5 years. Trial had to be stopped because of the large number of recurrences during the second 5 year period.

2. Trial compared chemotherapy with 5 years of tamoxifen, no differences found.

3. Swedish study looked at 5 versus 10 years of tamoxifen, no difference except for increased number of uterine cancers.

4. Ongoing British study is comparing shorter with longer intervals of tamoxifen, this study is basically relying on the power of numbers to determine the best course of treatment.

Recommendations:

1. Because flax seed oil goes rancid rather quickly, take flax seeds and grind them. This is probably more biologically meaningful than using the oil.

2. Dr. Block is just finishing a full nutrition manual, but research changes so fast that it is hard to keep publications up to date. He recommends books by the Commonweal Community.

3. Another book recommendation is a diet cancer book written by NCI researcher, Dan Nixon. 80% of the book is risk reduction, mainly preventative.

4. According to Dr. Tripathy, reading a comprehensive compendium is very confusing. The bottom line is that your individual risk remains unknown. You need to make a personal decision to improve your own personal risk by mind/body stress reduction; radical diet change; or pharmacology. It is almost impossible to do it all. It is more important to base your program on deep personal beliefs and preferences.