John R. Lee, M.D. Medical Letter August 98

Insights, Opinions, News and Reviews from John Lee and Friends

August 1998


In the interview with Dr. Kent Hermsmeyer, he brings us news from a menopause symposium held in Florence, Italy in June. It seems that a paper was presented there showing that Premarin contains over 100 active ingredients, including significant amounts of natural progesterone. This news gave me the best laugh I've had in awhile. But it is also a sobering example of information that physicians should have had many years ago in order to provide the best possible care to the women they're seeing.

Premarin has been a focus of much of the “estrogen research” conducted over the past twenty or so years, but now we know that we can't automatically assume that the results apply to estrogen. All that Premarin studies really give us, is information on a hormone cocktail made of about half human estrone, and half pregnant mare's urine that contains many active ingredients.

And don't assume that because Premarin contains some progesterone that you automatically have all of the protection conveyed by progesterone. There's sure to be some effect, but since it is taken orally much of it is lost, and the amount is too small relative to the excessively high dosage of estrogen found in Premarin.

The topic of women and heart disease is another area of medicine where all is not what it seems to be, and women often get short shrift. Let's examine this important topic more closely.

You can cause or help prevent cardiovascular disease, depending on the hormone you choose.

I'm about to give you a lot of seemingly discouraging statistics about women and heart disease, but stay with me — by the end of this article you'll know a lot about how to prevent heart disease.

The rate of death from heart disease in the United States has gradually declined over the past 20 years, but that decline has been much steeper for men than for women, and from 1992-1995, death rates from heart attacks in women increased. Until a few years ago, doctors didn't take heart disease symptoms in women very seriously — one out of three of them didn't even know it is the leading cause of death in women, more than all other causes of death combined. Eventually, with age, approximately 50 percent of women die of heart disease.

Women are more likely to die of a first heart attack, and two-thirds of them have no previous symptoms, compared to only half of men who have no previous symptoms. Some people guess that the women do have previous symptoms, but either don't go to the doctor for them, or the doctor doesn't take them seriously. It is also possible that the cause or mechanism of women's heart problems is different in some way to that of men.

One year after a heart attack, 44 percent of women have died, as compared to only 27 percent of men. Although women tend to live about seven years longer than men, they spend twice as many years disabled before they die.

We don't know whether taking aspirin prevents heart disease in women. We do know that hysterectomy, with or without the removal of the ovaries, leads to a much greater risk of heart disease, and that this risk is somewhat, but not entirely, lessened by taking estrogen.

Challenging Hormone Dogma
The prevailing dogma about women and heart disease has been that it increases rapidly after menopause, and the assumption is that this is due to estrogen deficiency. However, Harvard researcher Meir Stampfer, M.D., recently presented a controversial paper at a menopause symposium in Florence, Italy, showing that a woman's increasing risk of heart disease is correlated with age, but not with menopause. What makes this intriguing to me is that his information was based on pre-1985 data, and more recent data shows that there is a correlation with menopause. Some research shows that women's risk of heart disease eventually exceeds that of a man's. Has something created a correlation between death from heart disease in women and menopause since 1985?

Women's Symptoms Point to Spasms
It is oxidized LDL cholesterol that clogs the arteries and leads to a heart attack. However, only 50 percent of coronary artery disease (CAD) deaths are associated with clogged arteries, and the majority of those are men. Autopsies show that plaque-obstructed arteries in women are considerably less clogged than those of men, most often only 20 to 30 percent blockage, which is not sufficient to cause their deaths. Men, by contrast, tend to have more than 90 percent occlusion when they have a heart attack.

Chest pain is the most common symptom of heart disease and heart attack in both men and women, but women having a heart attack are more likely to complain of upper abdominal pain, difficulty breathing, nausea and fatigue. Syndrome X is a cluster of heart disease symptoms that almost exclusively affects menopausal women. The symptoms of women with Syndrome X include exertional angina (chest pain in response to exercise) and a positive response to diagnostic exercise testing, and yet they have clear coronary arteries.

Prior to menopause (surgical or otherwise) women may have what are considered to be heart disease risk factors such as high cholesterol and blood pressure, yet they rarely die of a heart attack. So how do women die of heart attacks after menopause? Perhaps we can take our clue from research done by our “Researcher of the Month” this issue, Dr. Kent Hermsmeyer, and others.

Provera Makes Arteries More Prone to Spasm
Hermsmeyer and his colleagues set out to study the effect of hormones on coronary artery spasm. They removed the ovaries from 12 rhesus monkeys to simulate menopause. Then six of the monkeys were put on estradiol (an estrogen) and natural progesterone, and six were put on estradiol and the synthetic progestin medroxyprogesterone acetate or MPA (Provera). Four weeks later the monkeys were injected with a combination of serotonin plus a platelet extract (thromboxane A2) known to stimulate coronary artery spasm. The monkeys that were on MPA and estrogen suffered from an unrelenting spasm that would have caused death had they not been injected with a drug that reversed the spasm. The monkeys that had been treated with estradiol and natural progesterone showed very little coronary artery spasm.

These findings are echoed by work done at Wake Forest University’s Bowman School of Medicine in Winston-Salem, NC, led by J. Koudy Williams. Their research with monkeys, heart disease and hormones has shown that medroxyprogesterone “can obliterate the beneficial effect of estrogen therapy on the progression of coronary artery atherosclerosis,” which is clogging of the arteries.

At London's National Heart and Lung institute, in a study led by Peter Collins, women on different combinations of hormone replacement therapy were put on a treadmill. Once again, those who were using natural progesterone with estrogen could exercise significantly longer than those who took medroxyprogesterone.

My hypothesis is that the increased risk of cardiovascular disease now associated with menopause may not be due to relatively minor cholesterol plaque or to hormone deficiency per se, but to increased risk of coronary vasospasm caused by synthetic progestins such as medroxyprogesterone acetate used in HRT. This does not ignore the effects of aging and the other factors listed in the box on this page, it points the finger at a dangerous drug.

There's absolutely no excuse for any doctor to prescribe Provera for HRT when we have this kind of data. HRT should include small, physiologic doses of transdermal natural progesterone, which will protect against coronary vasospasm, combined with very small amounts of estrogen, when needed.

I'll talk more about estrogen and cardiovascular health in future issues. For now it’s enough to say that when it comes to optimal cardiovascular health, some women may benefit from a small amount of estrogen. But it is quite probable that for many women, postmenopausal production of estrone in fat cells may be sufficient when supplemented with natural progesterone.

An Anti-Spasm Mineral
A deficiency of the mineral magnesium can greatly increase the chance of a coronary vasospasm, and it is also implicated in mitral valve prolapse. Magnesium deficiency is common but generally unrecognized in the US, and yet cardiovascular survival correlates with magnesium concentrations, and higher cardiovascular disease mortality correlates with magnesium-depleting factors such as diuretic usage, diabetes, digoxin therapy, alcohol, age, congestive heart failure, diarrhea, and dietary deficiency.

A daily supplement of 300 to 400 mg of magnesium is good preventive medicine. It should be taken with no more than twice the amount of calcium for optimal absorption.

I hope this information on women and heart disease will create controversy and commentary, inspire research, and most of all, save lives.

Other Factors in Heart Disease

Homocysteine: Homocysteine is a waste product of methionine that is normally converted into a safer compound for excretion in urine. If it isn't converted, it accumulates and contributes to heart disease. The B vitamins B6, B12, and folic acid play key roles in the conversion of homocysteine, and deficiency can cause high homocysteine levels. A good daily multivitamin will contain 50 mg of vitamin B6; 400 mcg of folic acid; and 1,000 mcg of vitamin B12.

Antioxidants: In the Nurse's Questionnaire Study and the Harvard Men's Study, those whose intake of vitamin E equaled at least 100 iu experienced 35 to 50 percent fewer heart attacks, and a more recent study from Great Britain showed as much as a 70 percent reduced risk. Vitamin E is especially effective because it is fat-soluble and thus more likely to supply oxidation protection to fatty compounds such as cholesterol. In considering the potential benefit of water-soluble vitamin and mineral antioxidants it is probably wise to include vitamin C and selenium, also. I recommend daily: 400 IU of vitamin E, 200 mcg of selenium, and at least 500 mg twice daily of vitamin C.

Oils: Many studies show the benefits of eating fish, nuts and seeds which contain heart-healthy oils, and olive oil. Avoid hydrogenated and unsaturated oils.

Veggies: People who eat more fresh fruits and vegetables, and more fiber, have less heart disease.

Alcohol: People who drink a moderate amount of alcohol have less heart disease.

Sugar and milk Eat a minimum of sugar and refined carbohydrates, and stay away from milk after puberty.

Iron: Excess iron can promote oxidation reactions that increase the risk of heart disease. Unless you are anemic, find a multivitamin without iron.

Exercise: Moderate, enjoyable exercise greatly reduces heart disease risks.

Weight: While true obesity increases the risk of heart disease, the moderate weight gain most women experience around menopause is not harmful.

[VH Note: For more by Dr. Lee on heart disease, read Dr. John Lee's Commonsense Guide to a Health Heart.]


By Virginia Hopkins

Use “Ibu's” with Caution
For women with menstrual pain, the over-the-counter pain-killer ibuprofen (Motrin), affectionately known by many as “ibu’s” is an effective way to relieve cramps. Like its cousin aspirin, it is a prostaglandin inhibitor which suppresses inflammation, and also has a muscle-relaxing effect. Unfortunately it also comes with the side effect of stomach irritation and bleeding, and may also cause ulceration in the intestines and the colon.

Taking ibuprofen as directed for just a few days a month is enough to cause chronic stomach and/or colon irritation all month long in many women. If you have been taking ibuprofen regularly and you also have cramps, heartburn, sharp pains, bloating, gas, diarrhea, and other symptoms of indigestion, try going without the drug for a few months to see if your stomach irritation clears up.

If you do take ibuprofen, be sure to take it with food to reduce stomach irritation.

A study published in the July 1998 issue of the American Journal of Gastroenterology found that an ibuprofen-like pain killer called ketoprofen (Orudis KT) may cause frequent and severe stomach and intestinal problems. In fact, 50 percent of those in the study taking ketoprofen developed “severe gastric mucosal injury,” and two out of 24 developed gastric ulcers.

What can you take instead of the ibuprofen? As was mentioned here last month, acetaminophen (i.e. Tylenol and non-brand name equivalents) doesn't hurt the stomach, but is very hard on the liver. And it doesn't work nearly as well as ibuprofen does for menstrual pain.

The herb kava is a safe, effective alternative for some women. Of course the best way to treat menstrual pain is to prevent it by maintaining hormone balance. (See What Your Doctor May Not Tell You About Menopause.)

Taking the Mystery Out of the Morning-After Pill
Making the contraceptive known as “the morning-after pill” available in the US has been challenging because of opposition by the religious right. But according to the New York Times, a small but brave company in New Jersey will soon be offering a prescription morning-after pill for about $20.

The Times reported that this pill works by preventing ovulation, but if the fertilized egg is the concern, it should be obvious that ovulation has already occurred.

The morning-after pill is a combination of synthetic estradiol (an estrogen) and a synthetic progestin in high doses. The progestin blocks the implantation of the fertilized egg, and the “pill” is stopped after 5 to 7 days. The sudden decrease of the high-dose hormones initiates a menstrual period, another factor terminating the pregnancy.

This form of birth control is based on the same principles that birth control pills are based on, which theoretically should apply to any high-dose combination of estrogen and progesterone or progestin.

Women with high blood pressure or a high risk of stroke should use caution when taking high doses of estrogens and synthetic progestins.

Oral Diabetes Drugs Can Harm the Liver
Oral diabetes drugs are casually handed out by conventional medical doctors to pretty much anyone over the age of 50 whose blood test shows even slightly elevated glucose levels. This is called a “pre-diabetic” condition, and it is certainly easier for the doctor and HMO to prescribe these drugs than to teach someone how to eat better and exercise — often a virtual cure even for actual type 2 diabetes.

But now we're learning that some oral diabetes drugs, far from being benign, can cause serious liver dysfunction. Doctors are being warned that patients taking acarbose (Precose) or troglitazone (Rezulin) should be monitored for liver problems. These drugs may also be dangerous when combined with other liver-damaging substances such as alcohol, acetaminophen, and hundreds of other drugs.

Why not take a brisk walk and eat some broccoli instead!

[VH Note: for details read Prescription Alternatives]

Researcher of the Month; R. Kent Hermsmeyer, Ph.D.

Protecting Your Heart by Using the Right Hormones

Dr. Kent Hermsmeyer is a Senior Scientist at the Oregon Regional Primate Research Center, and a Professor of Medicine and Cell and Developmental Biology at Oregon Health Sciences University. He has received numerous honors for his research, and has more than 130 publications to his name, many of them on the subject of the muscles of the heart and arteries. [2008 Note: Dr. Hermsmeyer is now president of his own research company, Dimera, in Portland, OR.]

In 1997 Dr. Hermsmeyer published a ground-breaking study in the journal Nature Medicine, showing that medroxyprogesterone acetate (MPA), the synthetic progestin known as Provera which is given to most menopausal women in combination with their Premarin (PremPro, PremPhase), made the muscles of the hearts and the coronary arteries of rhesus monkeys who had their ovaries removed more reactive and prone to spasm. This was in direct contrast to natural progesterone, which had the opposite effect, making coronary arteries less likely to spasm. This unexpected result has led Dr. Hermsmeyer to delve more deeply in his research into the effects of estrogen and progesterone on the cardiovascular system, both in primates and humans.

In June, Dr. Hermsmeyer attended a conference called “Menopause 98” in Florence, Italy, and he also shares some new and provocative reports from that gathering.

JLML: Dr. Hermsmeyer, when you did your research on hormones and vasospasms, were you looking for a specific outcome?

KH: Our goal was to examine the effects of specific HRT regimens, particularly MPA versus progesterone in the presence of estradiol 17b on the heart. So we were surprised to find that MPA had such a negative effect in contrast to the beneficial effect of natural progesterone on coronary reactivity in monkeys. We also didn't expect to find that progesterone alone, without added estrogen, is protective of the coronary arteries. But it is, and I believe that progesterone can be a very important part of decreasing the incidence of sudden heart death and cardiovascular disease in menopausal women. However, we hypothesize that this protection occurs optimally when the woman’s body also has sub-physiological levels of estrogen, and that the two hormones, progesterone and estrogen, work best together.

JLML: What have you found are the mechanisms by which estrogen protects the heart?

KH: I think there are probably multiple mechanisms. One is through the known alpha estrogen receptor, which we and others have shown exists in endothelial cells [cells lining the artery walls], and assists with endothelial function. Estrogen plays a role in producing important vasodilators, which tend to keep arteries from constricting for more than a minute. A second mechanism is that estrogen probably has additional actions which will be further revealed through the careful study of the recently discovered estrogen beta receptor. Third, it is also necessary to have a minimal level of estrogen in order to induce progesterone receptors and thus gain the benefits of progesterone. Progesterone receptors are unusual in that they are induced by estrogen acting on estrogen receptors.

JLML: That's right, and vice versa—progesterone stimulates estrogen receptors. What have you found regarding progesterone levels and heart protection?

KH: We were very surprised to find just how low a concentration of progesterone can be protective against vasospasm—at least in monkeys. Blood measurements of 1 to 3 nanograms (ng) per milliliter (ml) were protective, and even 1 ng per ml seemed to offer coronary protection in our studies. Luteal [mid-cycle] levels in normally cycling premenopausal women are of the order of 4 to 8 ng per ml. The assumption has been that it would be desirable to restore these premenopausal levels, but we're challenging that assumption, and asking the question, “What is the minimum level you really need?”

The recent Lancet article which stated that short duration (only 10 days) treatment with ProGest cream gave blood levels of only 1 ng per ml, was interpreted by the authors as a failure, because they assumed that they had to reach 4 ng per ml to be successful. In contrast, we interpreted it as a possible great success, because 1 ng per ml may be sufficient to be protective.

JLML: How does 1 ng per ml translate for women who are using progesterone creams?

KH: It is the level they found with twice daily applications of the dosage recommended by the manufacturers of ProGest, which is a ½ tsp, or 1 gram each.

JLML: That translates to what Dr. Lee recommends for postmenopausal women, which is about 28 mg of transdermal progesterone per day, although recently he has been recommending lower doses of 15 to 20 mg per day, or about 1/4 tsp twice daily.

You did this important research showing that Provera makes coronary arteries very reactive. Have you found any statistical correlation between the rate of heart disease in women and the use of Provera?

KH: I haven't, but there may be a couple of good reasons for that. What we're describing here is coronary vasospasm, and to have a vasospasm doesn't necessarily mean to have sudden heart death. In fact most of the time that doesn't happen. What does happen is the development of more reactive arteries.

It's also very hard to diagnose vasospasm as a cause of death. When people die of a vasospasm, the pathology report might conclude that there was no apparent cause of death. That is because the vasospasm will not be detected after artery fixation for pathology, and thus the only way you can diagnose vasospasm is in the cath lab, with a catheter in the heart.

Vasospasm is an abnormally persistent contraction that should, and often does spontaneously disappear, which means that it still goes undiagnosed. We're trying to figure out how to better diagnose vasospasm and get an idea of blood vessel reactivity in a readily usable, non-invasive way. We hypothesize that if we can diagnose reactivity that predicts vasospasm, we can better devise correct hormone replacement regimens for individuals, and women can have a very much improved quality of life, and a longer life.

Another reason that we haven't found a statistical correlation between the use of MPA and heart disease is that in the published human studies, researchers have not usually differentiated among the synthetic progestins in the data. MPA is grouped in with all the progestins. Another factor, which came out at the Florence conference, is that most American women are using Premarin, which actually contains progesterone, which might partially offset the negative effects of the MPA.

JLML: Premarin contains progesterone?

KH: Yes. Premarin was reported to contain a low level of real progesterone, perhaps up to 1 ng per ml, which may be the magic number for heart protection. So women taking Premarin may have been getting some of the protective benefits of progesterone all along. Perhaps that is why Premarin seems to work well in protecting against heart disease, as compared to other estrogens used in HRT regimens. There are estimated to be at least 100 active substances in Premarin, so there may be other protective factors in there as well. This emphasizes an important point: even the experts in the field do not know and have not yet adequately studied what concentrations of which steroids are protective.

JLML: The implications of this are that all the research done on Premarin was really research done on a combination of estrogen, progesterone and who knows what else? –a pregnant mare's urine cocktail.

KH: That's right, it is a complicated and variable mixture, so we actually know much less than we think we do about the specific effects of the various steroid hormones on the cardiovascular system.



Q: I read your article in the July issue about cholesterol, and enjoyed it, but my doctor claims that progesterone raises cholesterol levels. Is this true?

A: Natural progesterone does not cause elevated cholesterol and will, in fact, help maintain a healthy cholesterol profile. However, many of the synthetic progestins do raise cholesterol levels, and that is probably what your doctor was referring to. High cortisol levels caused by chronic stress can also raise cholesterol levels. [VH Note: for details see, Dr. John Lee's Commonsense Guide to a Healthy Heart]

Q: I have heard that progesterone might be helpful to men with prostate problems. What is your point of view on this subject?

A: Progesterone is vital to good health in both women and men. It is the primary precursor of our adrenal cortical hormones and testosterone. Men synthesize progesterone in smaller amounts than women do, but it is still vital. And yes, I believe it may be important in the prevention and/or treatment of enlarged prostate (BPH) and prostate cancer.

In the past five years, a number of men have called or written to me to tell me of their experience with progesterone. They report that their symptoms of an enlarged prostate such as urinary urgency and frequency decreased considerably and their sexual performance increased. Several men with prostate cancer have told me their PSA (Prostate Specific Antigen) level decreased and they have had no progression of their prostate lesions since using a progesterone cream, applied in a small dab in the perineum area once a day.

One man called to say his bone metastases are now no longer visible by Mayo Clinic X-ray tests.

Though I retired from active practice nine years ago, six of my former patients with early prostate cancer have been using progesterone cream (along with diet, some vitamin and mineral supplements, and saw palmetto) for more than five years and report their cancer has shown no progression.

All this caused me to review the endocrinology books in regard to hormone changes in older men. There I found that three changes seem to occur as men age: (1) progesterone levels fall; (2) estradiol levels rise; and (3) testosterone changes to the dihydro- form, dihydrotestosterone (DHT).

This suggests to me that research should be done to determine whether the fall in progesterone is primary to the other changes. If it were true that falling progesterone synthesis by the testes preceded either prostate hypertrophy or prostate cancer, then a trial of natural progesterone cream in men might show that it prevents these conditions.

I think that in the future we'll find that it is excess environmental estrogens that are causing the increase in prostate enlargement and prostate cancers, and that whatever we can do to avoid or oppose those estrogens will help us prevent prostate disease.

[Note fr VH: Dr. Lee later wrote Dr. John Lee's Hormone Balance for Men]

Q: Can a woman who is taking tamoxifen use natural progesterone cream?

Of course my recommendation is that women use natural progesterone cream to prevent and treat breast cancer, [VH Note: for details read Dr. Lee's What Your Doctor May Not Tell You about Breast Cancer.] But for women who are taking tamoxifen and want to continue, yes, physiologic doses of transdermal progesterone are compatible with tamoxifen. As you know, tamoxifen is a non-steroid, weak-acting estrogen that binds to estrogen receptors in the breast and supposedly reduces the risk of breast cancer. I say “supposedly” because two recent 3– and 4-year studies reported in Lancet found no difference in breast cancer incidence between the group using tamoxifen and the controls, contrary to the 2-year study reported in the US. In addition, tamoxifen increases the risk of endometrial cancer and blood clots, including fatal blood clots in the lung.

Note to Reader from Virginia Hopkins
Dr. John Lee was my great friend, mentor, co-author and business partner. This website is dedicated to continuing the work that Dr. Lee and I did together to educate and inform women and men about natural hormones, hormone balance and achieving optimal health. Dr. John Lee was a courageous pioneer who changed the face of medicine by introducing the concepts of natural progesterone, estrogen dominance and hormone balance to a large audience of women and men seeking answers to their hormone questions. Dr. Lee's books have sold millions of copies, and he has left behind a wonderful collection of writings from his newsletters that are, in large part, freely shared on this website. Enjoy!

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