Stress and Heart Desease Risk on Women

"Our study of female monkeys indicates that stress affects estrogen levels and can lead to the development of heart disease - even before menopause," said Jay Kaplan, Ph.D., professor of comparative medicine.

Kaplan said the women have traditionally been considered "immune" from heart disease until after menopause, when their estrogen levels dramatically drop. His research showed that stress can actually reduce estrogen levels much earlier in life and cause the buildup of fatty deposits in the arteries that can lead to heart attacks and strokes.

"This research demonstrates that a deficiency of estrogen before menopause places these females on a high-risk trajectory, regardless of whether they get estrogen treatment after menopause," said Kaplan. "Our data and recent trials in humans suggest that the emphasis in this country on postmenopausal estrogen treatment may be misplaced."

In the study, female monkeys were placed in groups so they would naturally establish a pecking order from dominant to subordinate. Monkeys that were socially stressed - because they were in subordinate roles in their group - produced reduced amounts of the hormone estrogen. In women, the estrogen produced before menopause helps protect against heart disease and osteoporosis. Kaplan's results showed that the estrogen-deficient monkeys had four times more atherosclerosis than dominant monkeys that produced normal levels of estrogen. When the subordinate, or "stressed," monkeys got estrogen treatments either before or after menopause, their rates of atherosclerosis were cut in half. When they got a "double dose" of estrogen - both before and after menopause - their rates of atherosclerosis were equal to the dominant monkeys.

"Applied to women, this lifetime study suggests that having an estrogen deficiency in the pre-menopausal years predicts a higher rate of heart disease after menopause, even when treated with hormone replacement therapy after menopause," said Kaplan.

An ongoing study of human autopsy results supports Kaplan's findings. Results released last year showed that by age 35, one-third of women have substantial atherosclerosis in the vessels leading to their hearts.

In women, stress, anorexia nervosa and hormone imbalances can all reduce estrogen levels to the point that menstrual periods stop. But Kaplan and colleagues theorize that more moderate drops in estrogen - that don't produce symptoms - can also affect health.

"We know from monkey studies that stress can lower estrogen levels to the points that health is affected, even though the animals still have menstrual periods," he said.

In a study of 66 women having normal-length menstrual periods, estrogen levels were low enough in half of the participants to cause the bone loss that can lead to osteoporosis. Kaplan theorizes that if reduced estrogen levels can cause bone loss in women, they can also cause atherosclerosis.

In Kaplan's monkey study, estrogen was given in the form of oral contraceptives prior to menopause. After menopause, it was given as hormone replacement therapy. Monkeys were selected for the study because they closely resemble humans in behavioral and reproductive characteristics. The cynomolgus macaques, used in the study, have a 28-day menstrual cycle and the females (except stressed subordinates) have a natural resistance to heart disease compared to males. The research was funded by the National Heart, Lung and Blood Institute.

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The Estrogen Controversy and Causes of Breast Cancer

No one knows what causes breast cancer, and no one can clearly say why we are seeing an increase in breast cancer cases. More women develop breast cancer than men — about 100 cases in females for every one in a man. Women’s bodies make more estrogen than men’s. Therefore, the conventional wisdom has been that estrogen causes breast cancer.

Some would label this guilt by association; many direct links are missing. One of the biggest missing links is that women’s estrogen levels actually fall as they age, decreasing dramatically after menopause, but the incidence of breast cancer increases with age. The risk ratio that we all hear about — that one in eight women get breast cancer — is for women over 90 years of age. The rate for women in their 50’s is more like one in 50.

So obviously there is much more than estrogen going on in the development of breast cancer, and it is being over-simplistic to think of estrogen as a bad poison when it comes to breast health. Estrogen is a very beneficial hormone in general — it stimulates tissues to grow when we need it to, and it is also a helpful player in response to stress. Let’s explore what we know about the causes of breast cancer, what we don’t know, and what this may mean for you.

Hormones and breast cancer

What we don’t know, but researchers are studying, is how estrogen works in the breast tissue. We now realize that estrogen is probably secreted or produced directly from breast tissue — some from the fat of the breast, some from the ducts themselves. How and why this production continues throughout life is unknown. We also now realize that the body has many self-regulating or balancing mechanisms — that one hormone is usually balanced by another.

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In the uterus the estrogen that stimulates the uterus to grow is then balanced by progesterone which stops it. Unfortunately the mechanism may not be so simple in the breast. Breast and uterus are two very different tissues and the breast does not shed its lining once a month (thank heavens we do not need Tampax or Kotex for the breast each month!), but I still think the body works by self-regulating in some way.

Provera - a synthetic progestin (the natural compound was changed to make it patentable) — has been shown to increase breast cancer risk in several studies, and appears to be the bad actor in Prempro in the Women’s Health Initiative study. (Prempro is a combination of Premarin and Provera, both synthetics.) Why a small change in the synthetic compound should make this big a difference is confusing and distressing and needs more attention. However, natural progesterone has just not been studied that well.

There are definitive studies that bolster the connection between HRT with high doses of progestins and a reoccurrence of breast cancer. One trial, the HABITS (Hormonal Replacement Therapy — Is It Safe?), was stopped at the median follow-up because the risk of reoccurrence was 3.3 times higher than in women receiving no treatment or HRT with low-dose progestin.

In another study on progesterone and menopause, researchers compared the effects of topical progesterone cream to prescribed oral progesterone on a small group of 12 healthy post-menopausal women. Data revealed that the OTC progesterone cream resulted in similar progesterone blood levels as the prescribed oral form. The women also had the same rate of adverse side effects. The complete results of the study were published in the June 2005 Journal of Clinical Pharmacology.

What this tells us is that we still don’t fully understand how progesterone is metabolized in our bodies or how the pathway changes as we age.

One thing we do know is that nature did not intend for women to maintain high levels of progesterone after menopause. Artificially doing so may pose additional health risks depending on your health history. Consequently, we don’t recommend using progesterone of any kind for more than 12 months if you’re post-menopausal. (For more information, see my article on progestins, progesterone, and breast cancer.)
The complexities of estrogen

Another big problem is that all estrogen is lumped together as one entity — but estrogen made by human ovaries is different from a pregnant mare’s (the type used in Premarin), as well as the estrogens from plants (phytoestrogens) or environmental estrogens from breakdown products of chemicals in pesticides or cosmetics (xenoestrogens). These xenoestrogens may play a critical role, as they boost effective estrogen levels above normal levels and interfere in unknown ways with estrogen metabolism.

The fundamental structure of estrogen, for those who remember basic biology, is a steroid ring which can have different carbon and hydrogen molecules attached. These little differences between our estrogen and synthetics or xenoestrogens can confuse the body and create havoc — like the DES story.

There were some women in the WHI study who tolerated Premarin, which is a much stronger estrogen than the body is used to, without problems — their bodies metabolized it, used it, and then excreted it without obvious difficulty. Other women didn’t like how the synthetic hormones made them feel and stopped using them. For others, something stimulated their breasts to make cancer cells. But what we don’t know is what caused that errant growth, how or why. Do certain women have a genetic error that doesn’t let them process synthetic estrogens or xenoestrogens? We just don’t know — so the NIH decided it was safer to take all women off Prempro and Premarin because of the increased risk of breast cancer and other serious diseases. They are still investigating the difference between Premarin and bioidentical estrogens. We do not know if bioidentical hormones also increase the risk. There is no evidence that they do, and we believe because they are more natural that they are safer than synthetic hormones, but frankly, more study is needed.

I have had a few patients who developed breast cancer while using “natural” hormones. However, the vast majority of women who use these bioidentical forms feel that their quality of life benefits outweigh any unknown risks.

Another missing link in the blame-estrogen theory is that estrogen is not just one natural formula. There are at least three estrogens, known as E1, E2, and E3, or by the names estrone, estradiol, and estriol. Confusing? Yes — medical students learn this in about one hour in medical school, gynecologists learn a bit more in their training, but few really understand the differences. And wait, there’s more — which is even less well understood by your doctor, unless she or he is a biochemist.

Estrogen is broken down into metabolites which are then excreted in your feces or urine. Some of these metabolites have been found to be more carcinogenic than others and their ratio may be the most important factor. Sound familiar? It reminds me of cholesterol — where we have the good type and the bad type and the ratio of the two is what matters. Estrogen metabolites can now be measured in the blood or the urine and different dietary maneuvers made to improve the ratio. These tests are just coming onto the scene in conventional doctors’ offices.

We know from cell biology that most bodily processes require simple cofactors to keep things going. These cofactors are basic vitamins and minerals, some made by the body and others required from the diet. Our diets have drastically changed from our ancestors’ and even our parents’, and that is why we and the American Medical Association recommend a high-quality multivitamin for everyone.

Estrogen metabolism is not simple and has not been well studied. (For a good review of the gender differences in science, read Eve’s Rib, by Marianne Legato, MD.) Unfortunately, women subjects were considered too difficult to use in many clinical trials of the past, primarily because their hormones just changed too much to be “standardized.” Problems with “The Pill” research and early estrogen supplementation are also well documented in Barbara Seamen’s The Greatest Experiment Ever Performed on Women.

Hopefully, with more women in medicine — half of medical students now are women — more attention will be paid to women’s issues. And with computer technology data can be collected and tabulated with greater ease than in the past. But we need to keep asking the questions. You can ask your healthcare provider these questions and preface it with, “I don’t expect you to know the answer, but don’t you find it interesting?”

It is my personal opinion, based on nearly two decades of practice, that it cannot be just estrogen but other factors in the body, using, balancing, controlling, or feeding estrogen which are key to the development of breast cancer.

The truth is that we’re pretty early in the process of discovering the causes of breast cancer. At the moment what we know is modest compared to what we don’t know. It’s going to be complex — like women! Perhaps the answer is right in front of us and we just aren’t wearing the right colored glasses to see it. But to blame estrogen may be unfair and even dangerous because we lose sight of the real culprit or culprits.

What does this mean for you?

First, keep in mind that the best way to support healthy endocrine metabolism is with adequate nutrition, exercise and stress relief. You can get our guidance on these subjects in the Personal Program. We are often asked by women who have had breast cancer or have a family history of breast cancer if our Personal Program is for them. I give it a 100% approval. The Essential Nutrients are a high-quality multivitamin and multimineral complex — I find nothing in them that would interfere with chemotherapy treatments or hormonal therapies. If your oncologist warns you off them we suggest you provide him or her with the ingredients list and ask what it is they oppose in them and to give you documentation of it. Now if this sounds like a battle you don’t have the energy for, then follow your intuition and let it go for now.

Second, don’t be afraid of all forms of hormonal supplementation. There’s no evidence that bioidentical estrogens increase the risk of breast cancer or of recurrence. For breast cancer patients or those at high risk we recommend supplementation with caution and careful monitoring. Similarly, bioidentical progesterone can be very helpful with myriad symptoms of hormonal imbalance, especially when used in an initial restorative phase. We don’t recommend long-term use by breast cancer patients or those at high risk for breast cancer without monitoring blood hormone and metabolite levels.

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