Cardiovascular disease kills approximately 485,000 women per year in the age range of forty to sixty-five, compared to 60,000 deaths annually for all reproductive cancers combined: breast, uterine, ovarian, cervical, and vaginal cancers. Over age fifty, heart disease accounts for 53 percent of the deaths in women. Compare this with the 4 percent of deaths due to breast cancer in women over fifty. Consider these recent findings:
• Almost 50 percent of women in the United States have had a hysterectomy by age fifty. Even for those women who have not had their ovaries removed, about 65 percent will have menopausal estradiol levels by three years after surgery, regardless of age at which surgery was performed. This means that a woman who has a hysterectomy at age thirty has a better than 60 percent chance of being menopausal by age thirty-three, not the average age of fifty-one for natural menopause. Their heart disease risk more than doubles when they become menopausal, not at the older ages we typically associate with heart disease in women.
• Women in their thirties and forties, even though still menstruating, are beginning to show the early effects of declining estrogen that predispose them to higher risk of heart disease after menopause: rising total cholesterol, dropping levels of HDL (the “good” kind), rising levels of LDL (the “bad” kind), and rising blood pressure. Hormonal factors, in particularly estradiol levels, are usually not even considered until after menses cease, missing an important window of opportunity for reducing disease risk and preventing serious heart attacks through diet, lifestyle, hormonal and medication approaches.
• A 1999 Yale study of 384,878 hospital patients showed that women ages thirty to forty-nine who suffer a heart attack are more than twice as likely to die of it in that first hospitalization than are men of the same age. Previous studies had shown that women in general are more likely to die than men following a heart attack but this is the first study to show that this result also applied to such younger women. It is particularly alarming that doctors assume this younger age group of women is low risk for serious heart disease, and therefore don’t evaluate them as carefully or treat as aggressively as they would men with similar symptoms.
• Women with a serious, but commonly overlooked, metabolic disorder called PCOS, or polycystic ovary syndrome, are at especially high risk of having an early heart attack. PCOS causes waistline weight gain, high blood pressure, high androgen levels, insulin resistance with glucose intolerance, and marked increase in risk of diabetes mellitus.
• Women who present to medical offices and emergency rooms with complaints of palpitations are far more likely than men to be given a diagnosis of “anxiety,” a prescription for Valium or Xanax, and sent home. Tragic cases abound of women such as this then having a massive heart attack. Some have died as a result of misdiagnosis. I have had many women referred to my practice who had been labeled “anxious,” only to find on further evaluation that they had significant early cardiovascular disorders that required different medications, or they had perimenopausal decline in estradiol that needed hormonal management.
• Commonly, women in their forties and fifties who describe experiencing palpitations, chest discomfort or pain, and other cardiovascular symptomatology are not given the same degree of comprehensive evaluations and treatment options that are offered men. They are more likely to be given serotonin-boosting antidepressants rather than medications to lower cholesterol or restore estradiol balance.
• Recent studies in the gender differences in health care patterns indicate that women are less likely than men to be offered angiography, angioplasty, and cardiac bypass surgery. This is thought to be an additional factor to explain why more women die of their first heart attack compared to men.
• In another 1999 study at Manhattan’s St. Luke’s Roosevelt Hospital Center, women of all ages were found to have harder-to-diagnose symptoms and more complications of heart disease (internal bleeding, congestive heart failure) than were men. Women need to be especially vigilant about having thorough medical evaluations when they experience less recognizable potential heart attack symptoms such as unexplained sweating, nausea, or shortness of breath.
• Alcohol is known to have specific toxic effects on heart muscle fibers, and excessive alcohol consumption is increasing alarmingly in women. Alcohol is more damaging to women, ounce for ounce, than men because women have less of the enzyme that detoxifies alcohol in the body. Yet women are less likely than men to be identified as alcohol abusers at early, treatable stages of the illness. Women aren’t as commonly referred for alcohol treatment until later stages of alcoholism when cardiac and other severe complications have already occurred.
The myth of heart disease as a man’s problem, or only affecting older women, appears to be part of the reason that women of all ages with heart disease are sicker when the problems are recognized and have a higher death rate when they have a first heart attack compared to men with first attacks. The myth also helps to explain the overlooked serious heart disease emerging in women in their thirties. Far more women silently, and without much press attention, die of heart disease every year. These alarming trends in heart disease statistics have been present for decades, but women are still more aware of and fearful about breast cancer than about heart disease. Perhaps this difference directly results from the greater publicity and media attention given to breast cancer in women. Another reason women view heart disease risk less seriously than breast cancer is that many people have the mistaken belief that heart disease is a “quick and painless” way to die, compared to a prolonged, painful death from breast cancer. Yet, more women than men with heart disease have incapacitating pain, disability, loss of independence, and a prolonged death due to congestive heart failure, angina, or the complications of multiple small strokes. Heart disease may be just as slow, painful, and debilitating as breast cancer is perceived to be.
A significant decline in estradiol will increase your risk of heart disease, whatever your age. When hormone imbalance begins is the best time to evaluate your objective risk factors, not waiting until after problems develop. If you are armed with knowledge, each of you has a unique opportunity before actual menopause to identify potential risk factors for cardiovascular disease (CVD) and to implement lifestyle changes at a time when preventive approaches can be the most meaningful for your long-term quality of life. But if you are not aware that heart disease can affect women so dramatically, you may not know to discuss these issues with your physician. And physicians, like all the rest of us, had been taught to think of heart disease as a man’s disease that did not affect women until sometime after age sixty-five. This misconception still persists, years after the first edition of my book in 1994. You can do something to reduce your risk of these problems, so pay attention to the voices of women in this chapter as they share their stories and comments. Insist on having the proper evaluation by your physician.
Unfortunately, it has been only in the last few years that women have been included in studies of heart disease risks, as well as clinical studies of new medications to treat heart disease. The information we have shows that women have similar risk factors as men, except for estrogen. This seems so blatantly obvious that it is appalling to consider that the role of estrogen in heart disease has been studied only in recent years. Later in this chapter I will talk further about what we have come to understand about estrogen’s specific role in reducing risk of heart disease. The general risk factors for heart disease are summarized for your review in Table 1 below. There is a wealth of good books and pamphlets describing each of these risk factors and ways you can modify your lifestyle habits to reduce your risk.
Let me say at the outset: Having a healthy level of estradiol is a critical factor in reducing your risk of serious heart disease. But, before you think of hormones as a “magic bullet” for heart protection, I think it is crucial to make healthy lifestyle changes. These are the first and most important steps you can take to help prevent disability or premature death from heart disease. At least eleven of the CVD risk factors below are either modifiable or can be eliminated altogether by eliminating the unhealthy lifestyles that are so typical of Americans. Focus on making positive changes, and “JUST DO IT,” as the Nike ad says. Your health is your greatest wealth, and you are in control of protecting your investment.
Putting women’s risk factors in perspective shows the importance of studying gender differences: Total cholesterol levels are better predictors of CVD risk for men, but not for women. High levels of triglycerides are an independent risk factor for women, but not for men. Low levels of “good” HDL are a greater risk factor for women, while high LDL (“bad” cholesterol) levels are a greater risk factor for men. Among diabetics, high triglyceride levels increase heart disease risk nearly two-hundred-fold in women, but only about three-fold in men. A person who has the “lipid triad” of high total cholesterol, low HDL, and high LDL is thirteen times more likely to have an acute myocardial infarction (heart attack) in the next four years. What can you to improve your lipid triad? Stop smoking, start exercising, reduce dietary fat and sugars, and for women, consider estrogen therapy. By the mid-1990s, the National Cholesterol Education Program (NCEP) advised that estrogen therapy should be considered for women to lower LDL and raise HDL before using lipid-lowering drugs, such as niacin, Mevacor, Pravacol, Lipitor, Zocor, Lescol, or others.
Paying attention to your cholesterol levels, and the ratio of your “good” HDL cholesterol to the total cholesterol is crucial. But newer studies have shown that half of all heart attacks occur in people with normal cholesterol levels, so for many years physicians have been looking for additional markers that will help us identify high risk individuals sooner. In a study published in March 2000 in the New England Journal of Medicine, researchers led by Dr. Paul Ridker in Boston found that C-reactive protein is a powerful predictor of future heart attacks if the highly sensitive form of the blood test is used (hs-CRP). Hs-CRP was an even better predictor of heart attack risk than some other measures we have been looking at in women: lipoprotein (a), homocysteine, and LDL cholesterol. C-reactive protein is a marker of inflammation of blood vessels, an important factor in triggering the damage that leads to heart attacks. Using data on over 28,000 post-menopausal women from the Women’s Health Study, women with the highest levels of hs-CRP had more than a fourfold increase risk of heart attack compared with women who had lower levels of this protein. These same researchers have found that even heart patients with normal cholesterol levels who take the medication Pravacol have lower levels of C-RP, and a lower risk of future heart attack, than did the women taking placebo. But if you are concerned about your risk factors for heart attack and want to have some of these tests, be sure and ask your doctor to order the highly sensitive C-RP blood test, since not all of the tests for C-RP are as reliable as the newer versions of this test.
Table I—CARDIOVASCULAR DISEASE RISK FACTORS
• family history of cardiovascular disease
• growing older
• history of chest pain, or prior cardiac problems
• cigarette smoking
• high-fat diets, especially saturated fats
• lack of exercise
• obesity, especially increased abdominal (truncal) body fat (waist-to-hip ratio greater than 0.85); in women, waist over 35 inches
• hypertension (high blood pressure)
• elevated cholesterol and/or low HDL (HDL is a better predictor of CVD risk for women than for men)
• elevated triglycerides (a greater risk factor for women than for men)
• diabetes or impaired glucose tolerance
• elevated insulin or exaggerated insulin response to simple carbohydrates
• elevated levels of highly sensitive C-Reactive protein (hs-CRP)
• elevated levels of lipoprotein (a)
• elevated levels of fibrinogen
• elevated levels homocysteine
• low intake or low levels of B vitamins and folate
• clotting abnormalities (coagulopathy)
• premature ovarian failure, or removal of ovaries prior to the average age of natural menopause
• presence of PCOS (polycystic ovary syndrome)
• hypothyroidism (causes high blood pressure and high cholesterol)
• chronic use of prednisone or other corticosteroids
• elevated ferritin (iron stores), whether from ending of menstrual bleeding, excess iron supplementation, or the hereditary iron storage disorder hemochromatosis
• emotional stress (causes increased coronary vasospasm, more so in women than men)
© Elizabeth Lee Vliet, M.D., 1995, revised 2000
Symptoms are the changes and sensations you experience, such as headaches, racing heart, clammy skin, pain, flushing, tingling, and a myriad of others. These changes may indicate a normal body response to an environmental stimulus or even to your own thoughts. These sensations may also be a potential warning of disease. Not all symptoms indicate disease, and not all diseases (at least in early stages) produce symptoms. Hypertension and osteoporosis are classic examples of diseases that do not produce symptoms until damage has already been done to the body by the disease process. One of my tasks in helping patients is to sort out what the symptoms may indicate, and what diseases could be present that are still silent and not yet producing symptoms.
Palpitations, those fluttering or pounding sensations in the chest that can be quite disturbing and frightening, are quite common as part of the heart response to the brain effects of declining estrogen in the perimenopause and menopause. In numerous studies, palpitations occur in anywhere from 40–60 percent of women in the pre-and perimenopause transition during times of the menstrual cycle when estradiol levels drop (bleeding days and around ovulation). For about 15–20 percent of women, palpitations may be the only symptom serving as a clue to the decline in estradiol. But the presence of palpitations does not necessarily mean you have cardiovascular disease. Palpitations may occur as a heart response to the bursts of adrenaline in the brain that occur with drops in estradiol. The increase in heart rate is a normal part of the fight-or-flight reaction; the brain sends a signal to other body organs that something is changing rapidly and is out of balance. Palpitations may also occur in certain types of benign heart disease such as mitral valve prolapse or in potentially serious types of heart disease such as atrial fibrillation. Such diverse diseases as anemia and hyperthyroidism may also produce palpitations through other mechanisms. Panic disorder is a biological condition of excess, and erratic, production of adrenaline-type compounds in the brain that may produce palpitations as I described for hormone changes. So palpitations as a symptom have many different causes. Some causes are just normal responses, but some causes of palpitations indicate more serious conditions. And the best treatment will be different, depending on the specific cause.
Yet, the symptom of palpitations is not often viewed as a possible endocrine-based one that can be caused by falling estradiol or excess thyroid hormone. If women are evaluated medically for the problem of palpitations, they are most often seen by internal medicine or cardiology specialists who check for the possibility of heart disease with cholesterol blood tests, physical exam, electrocardiograms, and exercise (treadmill) electrocardiograms. If nothing abnormal is found on these tests, women are then likely to be told that the cause of their symptoms is stress or anxiety. The average woman is not told that her symptoms may be related to menopausal hormone changes, and she typically does not get evaluated with FSH and estradiol blood tests. Listen to CC describe her experience.
CC was thirty-nine years old when she came to see me. She described
. . . terrible pounding sensations in my chest, and it feels like my heart is going to come right through my chest, it actually hurts it’s beating so hard. Then it will go away for awhile, and all of sudden it will come back. It seems to be worse at night, and the funny thing is it doesn’t bother me when I’m out jogging. My doctor did an EKG and tells me there’s nothing wrong with my heart; he said I’m just too much of a Type A person and I need to relax. But the stress isn’t worse now, in fact my life is really pretty good except I want to know what this is because it hurts.
CC had no history of any health problems, did not smoke, seldom had alcohol, did not use any street drugs, and regularly participated in 5K “Fun Run” activities in the community in addition to her daily jogging. Over the past year, she had increased her jogging to between six and ten miles a day, usually six days a week. She reported a lactose intolerance and had cut out dairy products about ten years earlier. With her exercise, she did not think she needed to worry about calcium supplements. She appeared to be healthy and quite fit, and I could not elicit any other problems or symptoms in going through the usual medical “review of systems” checklist.
She was still menstruating, and at her recent gynecological checkup for her annual pelvic and Pap, she said she had been told “Everything’s fine, you’re normal.” When I questioned her more about her menstrual periods, she said her periods had been a lot lighter and less frequent over the past two years that she had been running more. I asked if her heart poundings had any relationship to her menstrual cycle. She said, “Well, now that you ask, I have noticed that it seems to always get really bad the day or two before my period starts, and it will last a couple of days and go away. Sometimes it seems to hit again mid-month, then go away again. Other times it will be there occasionally in an erratic way.” Her complete medical evaluation, including a thyroid and cholesterol profile along with a Holter monitor of her heart activity for twenty-four hours, were normal. On the first day of her period, when her heart poundings were the worst, her estradiol level was 23 and her FSH 2.0. The low FSH along with the low estradiol is fairly common when women have unwittingly suppressed their ovaries’ hormonal function with significant increases in their exercise regimen. I was suspicious from her dietary history and her alterations in menstrual pattern and flow that she may have begun to have early bone loss, and I suggested she consider having a bone density test. She was shocked to find that she had a bone density, at age thirty-nine, one standard deviation below the bottom of normal for her age.
When we reviewed all of her information, I explained that the hormone levels were quite low, and I thought the drop in estradiol each month before her period likely triggered the brain burst of adrenaline that increased her heart rate. Since she also had these episodes at midcycle some months, I told her I thought she had the same heart response when her estradiol dropped with ovulation. From her history, I did not think she ovulated every month and this helped her understand why the palpitations did not seem to happen on a regular basis at midcycle. I thought her bone loss had developed gradually with her reduced calcium intake as well as the decline in estrogen when her exercise intensity altered her menstrual pattern and decreased her overall body fat percentage. She did not have any more serious underlying heart disease causing her palpitations.
After we reviewed all of her options and choices, she elected to take the low-dose oral contraceptives (with a lower progestin content) to improve her hormonal balance, maintain her bone mass, and help eliminate the estrogen drop with menses that triggered her palpitations. Needless to say, I also urged her to take calcium and magnesium supplements to help keep from losing further bone. She has done extremely well since then and has not needed further medical visits, since her palpitations have resolved. Her gynecologist agreed with her being on the oral contraceptives and plans to manage that with her as part of her annual checkup. I have seen quite a lot of patients like CC in my practice, and find this rewarding because I feel that together, in a physician-patient partnership, we are arriving at options that prevent the progression of disease risks. In my view, this is a great example of “A stitch in time saves nine.”
Another difference in the way cardiovascular symptoms appear in men and women is in the pattern of chest pain called angina. Men typically experience “crushing” chest pain, with pain that spreads down the left arm and up into the neck area. Women are more likely to have what is called silent angina, which does not produce this severe, crushing pain and does not radiate down the left arm and into the neck as we see in men. Women may just experience a “tightness” or “heaviness” in the chest, which can often be mistaken for anxiety if a health professional is not aware of these gender differences in the way angina can present. More often in women than in men, angina may be triggered by spasm of the coronary arteries caused by falling estradiol levels or even emotional stress. So the symptoms of angina as well as the causes tend to be different for women.
The difference in how angina pain is experienced by women compared to men may be due to differences in pain threshold, differences in pain pathways in women, effects of estradiol on the arteries themselves, or other factors we have not yet identified. But it is clear that this difference in the pain symptoms for women is one reason women with angina, or ischemic heart disease, do not get diagnosed early and then have more serious disease by the time it is found. If you are at high risk of heart disease and are experiencing this kind of chest pain, be assertive in pursuing an evaluation by your physician. Listen to what this woman went through.
Meg was forty-seven and terrified of having heart disease. Both her parents died of CVD. Her mother had a heart attack in her late forties and then died in her early fifties. Meg’s cholesterol was 337, triglycerides were elevated at 400, and her CHOL/HDL ratio was 5.5, much too high for a woman her age who had not had any sign of menopause or any menstrual irregularities. She was significantly overweight and had a high fasting glucose. She described physical sensations of angina (ischemia of the heart muscle) with even mild exertion. All of these risks placed her in the highest risk group for her age, yet her HMO physician would not authorize further cardiac testing to evaluate her further, even with her high risk of CVD. Her husband even went in to see the doctor and try and talk with him. When he came home, he said to his wife, “Meg, that man doesn’t like you!” They finally talked with the head of customer service at their insurance company, who agreed to reimburse her for the cardiac treadmill stress test she had been requesting and I had prescribed for her due to her many heart disease risk factors. This woman and her husband fought appropriately for what should have been done in her health care. Many patients, however, are more passive than this and simply do not realize that they need to speak up to the health insurance company about such matters. Remember that you are the customer, and you have the right as well as the responsibility to seek appropriate medical evaluation under your health coverage. If you are not being heard, it helps to send a complaint letter to the Insurance Commissioner for your state. Meg and her husband took these steps, and were finally heard. She had her cardiac testing and it showed evidence of blockage of the coronary arteries . . . in time for her to take aggressive steps to prevent a full-blown heart attack. She started estradiol therapy, lipid-lowering medications, a healthy weight-loss program, and a gradual low-intensity walking program. She is doing much better now, with major improvement in all her heart disease risk factors.
It helps to understand the basics of how the heart and blood vessels work so that when I talk about estradiol effects, you will understand the many ways that this important hormone works to help prevent heart disease. The circulatory system is basically comprised of a pump (the heart, a muscular organ about the size of your closed fist) pushing fluid (the blood) through a series of tubes of different sizes (arteries, capillaries, veins) to provide nutrients (e.g., oxygen, glucose) and remove waste products for all the cells, tissues, and organs of the body. This is boiling it down to its most essential aspects. In reality, the massive process of constantly circulating fluids to all parts of the body day and night is incredibly complex, with many different mechanisms for regulating it and keeping the critical balance of the many chemicals the body needs to work properly. It is too complicated to describe further in the short space of this chapter, but at least you have the big picture.
There has to be a force, called blood pressure (BP), that moves the blood fluid through the system. BP is measured by two numbers that provide us with information about whether the heart is having to work harder to pump the blood (high blood pressure, hypertension) or whether the pressure is too low to keep blood moving to the necessary organs (low blood pressure, hypotension, can cause fainting spells, lightheadedness, fatigue). The top number is the systolic pressure; elevation of this number is usually less serious since it may be briefly elevated by stress, anxiety, and pain as well as by the more serious disorder of hypertension. The bottom number is the diastolic pressure; sustained elevation of the diastolic pressure greater than 90 mm Hg indicates hypertension. An average blood pressure is considered to be 120/80 mm Hg, but most women (and many physicians) don’t realize this number is based on an average male. If we had carefully evaluated gender differences, we would find that the average healthy younger female may have normal blood pressures in the range of 110/60 to 110/70. Thus, women who have a blood pressure of 120/80 may actually have a pressure that is higher than normal for them.
What happens in the process leading to high blood pressure and arteriosclerosis (cardiovascular disease)? Arteriosclerosis (or atherosclerosis) is basically plaque buildup in the arteries. Plaque is a mixture of cholesterol-containing particles along with platelets and fibrin. These deposits cause a narrowing of the arteries, much like a wad of dirt partially plugging a garden hose. Cholesterol has several forms, and the “good” form (HDL) serves as a scavenger to carry away plaque from the arteries so it can be broken down and excreted by the liver. LDL, or “bad,” cholesterol serves to add more cholesterol to the plaque deposits lining arteries. When cholesterol levels are abnormally high and levels of the good HDL cholesterol are low, LDL deposits more cholesterol molecules along the artery wall. Since there isn’t as much HDL to clean up these deposits and take them back to the liver to be broken down and excreted, plaque builds up on the walls of the arteries. This means it takes more pressure for the blood to get through the arteries, which results in high blood pressure. The narrowing of the arteries due to plaque leads to reduced blood flow to tissues that deprives cells of vital oxygen and nutrients (called ischemia). Loss of oxygen damages or destroys cells (called infarction).
When the damaged cells belong to the heart muscle itself, this is called a myocardial infarction, or MI. When the damaged cells are in the brain, it is called a stroke. The entire process is quite complex, but this is a simple overview of the basics to help you understand the role estrogen plays in reducing risk of both CVD and stroke. Women may be affected by many different types of disorders affecting the circulatory system. These are other common examples and terms, which your physician may use. Make certain to ask for patient education material to read if you are told you have one of these problems.
• arrhythmias (heart rate, rhythm disturbances)
• hypertension (high blood pressure)
• hyperlipidemia (high cholesterol, low HDL, high triglycerides)
• ischemic heart disease (angina)
• myocardial infarction, or MI (heart attack)
• strokes, transient ischemic attacks (TIA) (cerebrovascular disease)
• peripheral vascular disease (e.g., thrombophlebitis, or blood clots)
• murmurs, heart valve problems (e.g., mitral valve prolapse)
Heart disease rates for women rise dramatically with declining estradiol, regardless of your age when this happens. Heart disease in women rises even more significantly in the years after menopause. Disability, discomfort, and loss of ability to be active every day, as well as premature deaths in postmenopausal women, could be significantly reduced if women were given adequate information about the cardioprotective effects of estrogen replacement therapy and had an individualized discussion of their risks of various health problems. Unfortunately, so many women have been frightened by the excessive reporting of the breast cancer risks that they are unwilling to consider taking estrogen after menopause. Even many health professionals are unduly swayed by breast cancer worries and fail to adequately explain to women their much greater risk of being incapacitated or dying from heart disease. Primary care physicians, in particular gynecologists working with menopausal women, can play a major role in correcting the misinformation among consumers. This would help women make informed choices about postmenopausal estrogen therapy based on their own individual needs rather than decisions based on fear, or decisions based on what friends may have decided about hormones.
There has been a great deal of exciting research in the last few years that has helped us now understand the many ways that the normal female premenopausal form of estrogen, 17-beta estradiol, exerts its protective effect on heart disease. You may have read about the way that estrogen reduces total cholesterol and increases the body’s production of the good type of cholesterol, HDL. But have you seen some of the latest findings?
• Estrogen decreases LDL, the plaque-forming kind of cholesterol, by increasing liver breakdown of LDL so that it is eliminated from the circulation. In a 1991 Harvard study of healthy postmenopausal women, oral estrogens reduced LDL an average of 15 percent, and increased HDL by 16 percent. Transdermal estradiol did not have the same magnitude of pharmacologic effect on HDL and LDL initially but does maintain the natural beneficial effects of estradiol over time to keep HDL and LDL in the premenopausal ranges. In addition, transdermal estradiol decreases the triglyceride levels, whereas oral forms of estrogen may increase triglycerides.
• Estrogen stimulates the production of HDL, the good cholesterol that carries plaque away from the artery wall and back to the liver to be broken down and excreted.
• Estrogen stimulates the formation of LDL receptors in the liver and possibly the walls of arterial blood vessels. These receptors bind the LDL so that LDL molecules are removed from the circulation and prevented from forming plaque.
• 17-beta estradiol acts as a calcium-channel blocker to relax artery walls, which helps to dilate the arteries, to improve blood flow throughout the brain and body, and to reduce blood pressure. Calcium-channel-blocking medications (many are on the market; some examples are Calan, Cardizem, DynaCirc, Isoptin, and Procardia) are used medically to treat a number of disorders such as angina, hypertension, migraine headaches, and bipolar mood disorders. Estradiol has a similar mechanism of action on the blood vessels’ calcium channels, so this may be one way estradiol performs its normal function of keeping blood pressure lower in premenopausal women compared to men of the same age. After menopause, as estrogen goes down, we see rises in women’s blood pressure more similar to the readings in men.
• Estradiol given sublingually (dissolved under the tongue) improves blood flow in the coronary arteries of the heart as well as women’s exercise tolerance on treadmill testing, an important finding demonstrated by Dr. Philip Sarrel of Yale University in collaboration with cardiologists in London. The women in these studies were postmenopausal women with previously documented coronary artery disease that had caused at least 70 percent occlusion of the arteries. Thus, the improvement seen with estradiol was even more impressive, given that these women had such severe disease.
• Estrogen stimulates the release of endothelium-derived relaxing factor (EDRF, thought to be nitric oxide) a chemical having an important role in dilating blood vessels to maintain normal pressure and flow. In a two-year study of twenty-six postmenopausal women, levels of this blood vessel relaxing agent kept rising in women on estrogen and continued to increase the longer they took estrogen. Levels of the nitric oxide compound were not changed in women who were not receiving estrogen. Dr. Raghvendra Dubey, of the University of Pittsburgh, who headed this study, said that their results helped to explain another way in which estrogen protects against heart disease before menopause and why it may be important to consider as therapy for postmenopausal women at high risk of CVD.
• Estrogen maintains the normal balance of prostacycline and thromboxane, two chemicals that regulate clot formation. Healthy clot formation is a protective mechanism, but excess clot formation leads to heart attacks and strokes. Prostacycline dilates blood vessels (improves blood flow and lowers blood pressure) and it also prevents platelets from aggregating or “clumping” and forming plaque to block the arteries. Thromboxane has the opposite effect: It constricts blood vessels and stimulates platelet aggregation as a means of defending the body against hemorrhage. When thromboxane levels are high, blood pressure goes up and more “sticky” platelets aggregate to form plaque along the artery wall. Estrogen increases artery production of prostacycline, which improves blood flow and reduces platelet clumping to form clots and plaque. Estradiol’s action is also similar to the way that aspirin works to help prevent clots and reduce the risk of strokes and heart attacks.
• Estrogen decreases fibrinogen, another clot-forming factor in the blood. Higher fibrinogen levels are associated with increased clot formation. The Post-menopausal Estrogen and Progestin Intervention Trial (PEPI studies) results released in January 1995 showed that fibrinogen levels rose by 3 percent in women not on estrogen. In the Framingham study of heart disease factors, a 3 percent increase in fibrinogen doubled the risk of heart attack in women. Women who were taking estrogen (Premarin) showed no change in fibrinogen levels in the PEPI study. More recent studies using transdermal 17-beta estradiol have shown that estradiol decreases fibrinogen.
• Estrogen therapy (to restore estradiol levels to premenopausal ranges) also improves clot-dissolving ability, based on recent analysis of the second generation of women in the Framingham Study. Premenopausal and postmenopausal women taking estrogen had significantly lower levels of plasminogen activator inhibitor (PAI-1) than women not on estrogen therapy. Since PAI-1 is a chemical that interferes with natural clot-dissolving ability, lower levels are desirable.
• Estradiol helps to modulate the various receptors involved in the fight-or-flight response that can lead to stress-induced spasm of the blood vessels to the heart causing angina in women. Along with this effect, estradiol helps to increase the forcefulness of the heart-muscle pumping action with each heartbeat (positive inotropic effect), and it also increases the “stroke volume” or amount of blood pumped with each heartbeat. Both effects mean improved blood flow to the body.
• Estradiol also helps to decrease total body vascular resistance, which also means improved blood flow to the entire body. This beneficial effect was especially enhanced when estradiol was given in the transdermal patch form.
• Transdermal estradiol has the same beneficial effects on HDL cholesterol as oral estrogen after about six months of transdermal therapy as shown in studies by Corson (1993) and LaRosa (1994). Corson and LaRosa also showed that oral estrogens may sometimes cause an unwanted increase in triglycerides, but transdermal estradiol helps decrease triglycerides (which lowers CVD risk).
• Transdermal estradiol significantly decreases both systolic and diastolic blood pressure as shown in a 1994 study by Cheang and coworkers.
• Estradiol has several specific effects on the coronary arteries to reduce the buildup of plaque and keep arteries healthy: Estradiol (E2) inhibits excess growth of arterial smooth muscle (too much smooth muscle makes the artery wall thicker and reduces effective blood flow); E2 inhibits deposits of elastin and collagen that provide a base for plaque formation to clog the artery; and E2 also inhibits lipids (blood fats) from accumulating in plaques in the artery wall. In addition, E2 stimulates up-regulation of vasorelaxin and down-regulation of vasoconstriction, which means lower blood pressure and better blood flow to the body.
• Estradiol has been found to act as a free-radical scavenger helping to break down plaque in arteries, demonstrated in a number of studies in recent years. This action is similar to the way other compounds with antioxidant properties (vitamin E, vitamin C) act to help prevent heart disease. In fact, a recent study published in Menopause: The Journal of the North American Menopause Society in 2000 (volume 7) found that the 17-beta estradiol made by our ovaries before menopause has an antioxidant potency at least 10–100 times greater than alpha and gamma tocopherol (vitamin E) and melatonin. No wonder younger women don’t have heart attacks. In addition to the importance of antioxidants in helping to prevent heart disease, I also talk about their role in cancer prevention (see chapters on nutrition and breast cancer).
All of these exciting developments indicate the depth of the worldwide research on how estrogen in women helps to maintain healthy heart and blood-vessel function throughout the body. Such research helps to better explain why heart diseases increase at menopause when women lose the most active form of estrogen, 17-beta estradiol. The newer research also helps us to understand why heart disease may hit younger women as well if they have conditions like PCOS that cause excess androgens and a relative decrease in the desirable estradiol effects. I am amazed at all the wealth of new information and research just in the five years since I first published this book, as summarized in the following chart.
SUMMARY OF ESTRADIOL (E2) BENEFITS
ON HEART DISEASE RISK
• E2 lowers blood pressure by dilating blood vessels
• E2 increases HDL (“good”) cholesterol
• E2 decreases total cholesterol and (“bad”) LDL
• E2 improves carbohydrate metabolism, decreasing risk of diabetes
• E2 reduces platelet stickiness and clumping that causes strokes, artery-clogging plaque; increases secretion of prostacycline
• E2 reduces risk of blood clots by several mechanisms
• E2 has antioxidant effects on artery walls
• E2 reverses the impaired vessel response to acetylcholine in atherosclerotic coronary arteries—Gender specific
• Estradiol enhances release of endothelium-derived NO (nitric oxide), a potent vasodilator; acts as calcium-channel blocker (vasodilation)
• E2 alters synthesis, release, and response to vasoconstrictive peptides (e.g., endothelin-I and angiotensin-II)
• E2 increases endothelial permeability, transport of blood-derived 02
© Elizabeth Lee Vliet, M.D., 1995, revised 2000
Millions of women in their twenties and thirties have a hidden disorder that dramatically increases their risk of heart attacks before menopause. What is it? It is polycystic ovarian syndrome (PCOS), a commonly overlooked condition affecting about 6–10 percent of premenopausal women, including teenagers, that results in widespread metabolic changes in the body. PCOS increases the risk of cardiovascular disease as much as eleven-fold by age fifty. Even women from forty to forty-nine years old who have PCOS are estimated to have a risk that is four times the risk for women in this age group who do not have PCOS. Syndrome X, a metabolic-endocrine disorder common in women, is another “mysterious” women’s disorder seen in premenopausal women and known to be associated with a particularly high risk of having an early heart attack. What are these conditions, and why haven’t you heard more about them?
Part of the reason PCOS has been so overlooked is that gynecologists have been taught in the past that a woman only had the possibility of PCOS if she had stopped menstruating (called amenorrhea). In addition, the most common reason women with PCOS see a physician is for infertility. So, if you are not trying to become pregnant, and still have menstrual periods, even though you may have all the other metabolic changes that go with PCOS, you are likely to be overlooked in our current fragmented approach to women’s health. Endocrinologists is this country haven’t focused much on the ovary, since this endocrine organ is the “turf” of gynecologists. Gynecologists, on the other hand, haven’t worried much about women who were perceived to have “just a cosmetic problem” of waistline weight gain and excess facial hair, or who skipped periods . . . the kinds of changes that occur in both PCOS and Syndrome X. To physicians trained as surgeons, and focused on helping you get pregnant and deliver your baby, these other problems just haven’t seemed very important, and they had been taught that PCOS interfered “only” with a woman’s ability to get pregnant.
So, what happened? Women who actually had a very serious disorder (that we now know affects far more than reproduction) were most often discounted and simply told to “not worry, everybody misses periods sometimes” or “just go exercise and lose weight and your periods will come back, and you’ll be fine.” This happened to a sixteen-year-old young woman I saw recently, who had severe hormonal imbalance, with a very high level of free testosterone, low estradiol, and a fifty-pound weight gain over six months in spite of a very healthy diet and extensive exercise regimen. She had PCOS, but her gynecologist had not recognized it, because he saw her as simply a teenager obsessed with weight gain. Many physicians don’t realize that PCOS has potentially devastating consequences for the rest of a woman’s life and could lead to early death from heart attacks or diabetes complications long before menopause. So it isn’t “just a cosmetic” issue, it may be your life at stake, as you will see later in this chapter with Susu’s story.
First described in 1935, PCOS, or Stein-Leventhal Syndrome, is characterized by excess body hair, lack of ovulation and regular menses, and multiple cysts on the ovaries. Today it is recognized as more than just ovarian cysts and irregular menses; it is a complex endocrine disorder with wide-ranging serious negative effects on fertility, body weight (with marked “middle-body” fat increase), blood pressure, diabetes and cardiovascular disease risks, and later risk of endometrial cancer. Today, we know that these diverse complications of PCOS are caused in large part by the elevated level of androgens, higher-than-normal free testosterone, high estrone-to-estradiol ratio, and insulin resistance with elevated insulin levels causing more vascular damage and abdominal weight gain. With this terrible vicious cycle, young women with PCOS are at especially high risk of developing diabetes, which in turn causes many damaging changes in the heart and blood vessels throughout the body and thereby increases the risk of having a premature heart attack or stroke. Syndrome X, now known to be associated with estrogen deficiency, has a similar picture in terms of causing a marked increase in risk of both heart attack and stroke in younger women. These combined conditions, both affecting normal ovarian hormone balance, affect millions of women, and cause untold pain and suffering, not to mention early death. PCOS and Syndrome X desperately need our careful attention as physicians to get these conditions better recognized and treated when women are younger, before they develop permanent problems.
Another cause of concern is that the very treatment of PCOS that is directed toward infertility may itself cause more problems for these young women. International climacteric medicine specialists have published reports that surgical treatments with laparoscopic ovarian diathermy and drugs to stimulate ovulation such as clomiphene citrate (Clomid) may cause premature menopause and a higher risk of ovarian cancer. Using higher-dose content of progestin in a birth control pill to regulate menstrual cycles in these women may lead to further development of lipid and triglyceride abnormalities, which increase risk of plaque buildup in the arteries, particularly if the pills contain higher amounts of the androgenic progestins. More on this issue in the next section on progestin effects in heart disease. So women with PCOS have a double whammy—they often need specialized treatment if they are going to be able to get pregnant, and some of the treatments themselves may lead to serious problems later.
Newer treatment options for PCOS, and potentially Syndrome X, offer more hope with fewer long-term risks. One promising option is the use of Glucophage (metformin) and other agents that improve glucose intolerance–insulin resistance. Metformin has been shown in a number of recent studies to lower abnormal insulin levels, improve triglyceride and cholesterol abnormalities, improve ovulation (and thereby fertility) and help decrease risk of diabetes and adverse changes in blood vessels. In a 1998 study published in The New England Journal of Medicine, 90 percent of the women who took metformin either ovulated spontaneously or with help from the fertility drug Clomid but only 12 percent of the women taking a placebo pill had ovulatory cycles, even if they also took Clomid. More studies are needed on the safety of these medications for the developing fetus, so women trying to get pregnant who want to be treated with metformin should discuss these issues with a fertility specialist.
We have used metformin quite successfully for many PCOS patients that we see at our HER Place offices. Although it is a drug more often used to help young women struggling with infertility, our gynecologist and I have found that it works well to reduce insulin resistance (and its complications) in women who are not necessarily trying to become pregnant. We often use metformin for our patients with PCOS and Syndrome X to help reduce the excess insulin that makes it so hard for these patients to lose weight. In turn, being able to lose weight helps decrease many of the risk factors for both diabetes and heart disease. Because the multiple health risks of PCOS and Syndrome X are so severe, I think metformin has an important role in the treatment of women with suspected PCOS, Syndrome X, or insulin resistance due to weight gain alone, without PCOS. In our experience, bothersome side effects have been relatively uncommon. We usually start metformin at a lower dose than the recommended amount because we find it works well and causes fewer side effects if we start low and increase slowly. Using it this way, side effects tend to be fairly mild (headaches, nausea, diarrhea) and typically disappear with just dietary changes and decreasing the dose.
It is encouraging to me that these newer treatments are so promising, with less reported risks so far than what has been seen with the more aggressive treatments I described earlier. I include all of this information in the heart disease chapter because both PCOS and Syndrome X are conditions that increase heart disease risks in younger women, and the common symptoms of missed menstrual periods, increased body/face hair, and weight gain are often minimized by physicians. If you have these symptoms, or had them when you were younger, keep in mind that PCOS is the culprit about 80–90 percent of the time, and you should be carefully assessed for heart disease risk factors now. The good news is that both disorders are very treatable problems if they are recognized early and an integrated approach to treatment begun.
The synthetic progestins have been added to postmenopausal hormone therapy regimens in order to reduce the risk of endometrial cancer of the uterus from taking estrogen alone. The drawback has been that the progestins have tended to offset the estrogen benefits on heart disease risks and to cause significant unwanted side effects such as breast tenderness, bloating, weight gain, loss of sex drive, and depression. These problems were particularly marked when higher doses of Provera (the standard progestin used in the United States) were common. The typical dose of Provera has been 10 mg daily for ten to fifteen days a month. Menopause specialists are now recommending that Provera be decreased to 5 mg daily for a cyclic regimen ten to fourteen days a month, and 2.5 mg if given every day for a continuous regimen. But even at these lower doses, there is still the potential to reduce estrogen benefits on the various heart disease factors I listed above.
To help you understand the concern, keep in mind that all progestins (even natural progesterone) have the potential to lower the beneficial HDL cholesterol, and also adversely affect glucose-insulin regulation and increase triglycerides, all of which are other potential heart disease risk factors. It was over a decade ago that we recognized that HDL was more important than total cholesterol in estimating CVD risk, but many physicians still only measure total cholesterol and don’t check the HDL. How does this omission affect you? Consider the following examples of two different women and their heart disease risk, and then ask yourself, is it important to know my HDL?
• A forty-two-year-old woman, total cholesterol 250
• A forty-nine-year-old woman, total cholesterol 250
Many women and their physicians would be alarmed by the total cholesterol and may rush into taking expensive lipid-lowering medications with the potential for side effects. But, one of these women really doesn’t need lipid-lowering medication, and one of them needs to start it immediately. These two women have very different risks for heart disease. How do you tell which is which? The key lies in their HDL level and calculation of their risk ratios from the total cholesterol number divided by their HDL number.
The forty-nine-year-old has an HDL of 89, giving her a CHOL/HDL ratio of only 2.8, about half average risk of heart disease. Her excellent HDL is about thirty points above the average for a woman her age. Why is her HDL so high? She is a nonsmoker, takes 17-beta estradiol alone (she had a hysterectomy several years ago so doesn’t need a progestin or progesterone), and she exercises regularly. She does not need any cholesterol-lowering medication.
The forty-two-year-old has an HDL of only 25, giving her a CHOL/HDL ratio of 10, more than four times average risk of heart disease in a woman, and a risk that requires immediate and aggressive intervention to help prevent a sudden heart attack or stroke. Why is this younger woman’s HDL so low? She is a smoker, doesn’t exercise, and has an estradiol level of less than 35, well below the level needed to maintain a healthy HDL level. Her low estradiol is likely a result of cigarette smoking suppressing her ovaries, increasing her risk for early menopause. Obviously, she needs to stop smoking now, but she really does need to be started on lipid-lowering medication right away to quickly bring up her HDL and to help reverse existing damage to the arteries. She is someone who would have even more risk if she were started on the standard menopause “cookbook” approach with Premarin and Provera or PremPro, due to the adverse effects of the synthetic progestin further decreasing her “good” cholesterol.
In addition to decreasing the HDL cholesterol, the adverse effects of progestins on the cholesterol profile are related to several factors:
• Duration of the dose. Taking the progestin every day, even at a lower dose, has a more negative effect on HDL, triglycerides, insulin, and glucose than does taking the progestin for only ten to fourteen days a month on a cyclic regimen.
• Degree of androgen-like properties. Natural progesterone and the new non-androgenic synthetic progestins (e.g., desogestrel) so far seem not to have as much of the unwanted effect of decreasing HDL, particularly if given transdermally, sublingually, or vaginally and if the doses used are in the therapeutic range for postmenopausal use. (This statement does not apply to the much higher pharmacologic doses of natural progesterone often used in treating PMS. I will say more about this issue later).
• Route of administration. Transdermal, sublingual, and vaginal types of progesterone bypass the liver and appear not to have as much of the adverse effects on HDL cholesterol, triglycerides, insulin, and glucose that occur when the progestin is taken orally. Oral progestin therapy is standard in the United States. The nonoral routes listed above are more the norm in Europe, where there are also a variety of forms of natural progesterone options as well.
The Postmenopause Estrogen Progestin Intervention (PEPI) studies, a three-year investigation into the benefits and risks of various hormone regimens, was the first major study in the United States to use natural micronized progesterone as one of the therapy regimens and to compare its effectiveness with the standard progestin, Provera. Investigators found that the natural micronized progesterone protected the endometrium (not surprising, since that’s what it did for women before menopause!) and did not have the drawback of decreasing HDL to the degree seen with Provera. In fact, micronized progesterone preserves 60 percent more of the estrogen-related benefits on cardiovascular measures than does Provera. Another finding of concern in the PEPI study was that the two-hour insulin and two-hour glucose levels were both significantly increased with the MPA (Provera) group, which is another mechanism by which progestins increase risk of both heart disease and diabetes. The results of this study were hailed as a major breakthrough in this country by those of us who have long been advocating the use of natural progesterone for postmenopausal regimens. Hopefully, now that Prometrium and Crinone brands of natural progesterone are available in the United States, we will now see more physicians using progesterone.
Natural progesterone, when given in the low doses currently recommended for menopausal regimens (these are as follows: Prometrium 200 mg orally for ten–fourteen days a month, or 100 mg orally if given every day, or Crinone vaginally 40 mg every other day for six doses a month) has not been found to have the adverse effects on cholesterol, triglycerides, glucose, or insulin that are seen with the synthetic progestins. But there is an important caution to any of you readers who are using natural progesterone in the much higher doses that are being recommended for PMS therapy. Doses in excess of 300 mg a day orally (or creams containing more than 20–40 mg a day) give blood levels of progesterone that are as high as those found in the third trimester of pregnancy. These higher doses of progesterone for PMS may cause high blood glucose and worsening glucose control in diabetics or women with insulin resistance, and may also cause high triglycerides, high cholesterol, and higher-than-normal insulin production. These changes are all known to increase risk of heart disease later in life. The problem is that many PMS specialists who recommend such high doses of natural progesterone are not checking serum levels of progesterone or monitoring the cholesterol-triglyceride profile or checking for changes in fasting glucose and insulin, so they miss the fact that these problems are happening.
If you doubt what I am saying about the potential for such problems with high-dose progesterone, simply recall two common pregnancy-related problems most women have heard about: (1) pregnancy-induced (“gestational”) diabetes, and (2) toxemia or pre-eclampsia, a very severe form of high blood pressure that can occur in the latter part of pregnancy. These two problems tend to occur in the last stages of pregnancy when progesterone levels are at their highest. So, although I encourage you to consider using natural progesterone instead of synthetic progestins for your HRT in an acceptable dose range (unless you have a medical reason that requires the potency of the synthetic progestins), it is important to be careful about using excess doses or progesterone for other purposes or prolonged use, especially if you are overweight or have diabetes, hypertension, or elevated cholesterol or triglycerides.
Sadly, the PEPI study did not have any groups that were using the natural, bio-identical 17-beta estradiol form of estrogen women have before menopause. Premarin was the only estrogen used throughout all five groups in the PEPI study, so some of the better outcomes on heart disease risk that have been found in other studies since that time (described above in the estrogen section) were not seen in the PEPI study. But even using Premarin as a less desirable form of estrogen, the overall PEPI results showed a 30 percent decrease in heart disease risk, even factoring in the negative effects of the synthetic progestin, MPA. Overall, the PEPI study showed that there was no increase (or decrease) in blood pressure for women on estrogen, whether with or without a progestin. This finding is in contrast to other studies using transdermal 17-beta estradiol that have shown consistent decreases in blood pressure in women on estradiol compared to women on no hormone therapy. Since Dr. Whitehead and his group showed many years ago that increased blood pressure was a potential side effect of the excess oral estrogen load for the liver when using conjugated horse-derived estrogens, the lack of better effects on blood pressure in the PEPI study is not surprising.
One finding of the PEPI study will be of interest to those of you worried about weight gain with hormone therapy. Even when the women were given the types of hormones most likely to cause weight gain (Premarin and Provera), none of the groups in the PEPI study of women who were taking hormones showed a gain in weight. The only group that gained weight over the several years of the study was the placebo group on no hormones! This also fits with more recent data showing that postmenopausal women on no hormones consistently have higher percentage body fat and more “middle body” obesity than do women taking hormones after menopause. Keeping your healthy premenopausal balance of estradiol, estrone, testosterone, and DHEA is an important part of successfully managing our tendency to get fatter as we get older. I have addressed more on this subject in chapter 17.
Have you heard the headline saying something like “estrogen therapy shown not to help women with heart disease”? Were you confused by this, especially after all the previous positive reports about estrogen therapy reducing the risk of heart disease? Most people were. What’s the scoop? The Heart, and Estrogen-Progestin Replacement Study (HERS for short) was a large, randomized, prospective study designed to test the effects of a combined daily estrogen-progestin regimen (they used PremPro) in postmenopausal women who already had coronary heart disease to see if the hormone therapy would prevent further cardiovascular events, such as heart attack. The HERS trial lasted for just over four years, with half of the women taking a placebo and half of the women taking PremPro containing 0.625 mg of conjugated horse-derived estrogens with 2.5 mg medroxyprogesterone acetate or MPA (the progestin in Provera and Cycrin). None of the women were given estrogen alone to compare estrogen by itself with estrogen plus synthetic progestin. To everyone’s surprise, including the researchers themselves, during the first year of the study, women taking the combined HRT had 50 percent more heart attacks than women taking placebo, and 3 percent more clotting problems. An interesting pattern emerged later in the study: During the last two years of the study, women on the combined HRT had 40 percent fewer heart attacks, results that were more in keeping with other studies showing hormone therapy has beneficial effects to reduce heart disease. HERS participants taking combined HRT had an 11 percent reduction in LDL (“bad”) cholesterol and a 10 percent increase in HDL (“good”) cholesterol. These were positive changes, though not as good as the improvements in cholesterol measures seen with estrogen alone in other studies, particularly when 17-beta estradiol is used. Since it takes on average about 1.5 to 2 years before a reduction in cholesterol will show a decrease in heart disease risk, it may be that the women in the HERS trial were not in the study long enough to see the full benefit of hormone therapy.
But there are other serious problems with the HERS design that I think have been ignored or glossed over by both the consumer and the medical articles on this important subject. Remember the studies I described earlier from Drs. Campbell and Whitehead, published in 1982? They clearly showed that the horse-derived estrogens had the potential to have much worse effects on heart disease risk measures (renin substrate, blood pressure, fibrinogen, elevation of triglycerides, et cetera) than did our own natural 17-beta estradiol. That information has been around almost twenty years, and yet the HERS researchers still chose to use only the horse-derived estrogen in the study. The blood-vessel-damaging effects of MPA have also been known for many years: Progestins like MPA reduce the beneficial effects of estrogen on a number of heart disease risk factors such as the good cholesterol levels, blood vessel wall elasticity, fibrinogen, and others. Natural progesterone is an available therapeutic option, and the PEPI studies published in 1995 showed that natural progesterone preserved at least 60 percent of the benefit gained by estrogen. Why wasn’t natural progesterone used in the HERS trial? Again, the HERS researchers still chose to use only the synthetic progestin in the study. No wonder consumers were confused. It is clear that the news articles didn’t give all this additional background. As a consumer, you should be aware that this study was funded by a grant from the company who makes PremPro. To those of us who have long advocated use of more natural forms of hormones for women, it was actually encouraging news to see our concerns demonstrated so clearly in the HERS results.
In using PremPro, HERS researchers were giving a potentially damaging combination hormone product to women who already had heart disease. Progestins are known constrictors of blood vessels, which tends to raise blood pressure and reduce blood flow—not a good combination in women who already had heart disease. And then we wonder why the women who participated had more heart attacks the first year. It seems odd that so many medical professionals expressed surprise at the findings. It seems to me that this result could have been predicted if someone had thought carefully about information that has been available for quite a few years. I was appalled that a study like this even passed the pretrial design review, with what has been published in the past about potential problems with daily progestins and heart disease, and also what has been published about potential adverse effects of oral horse-derived estrogens. I cited other studies earlier in this chapter that had shown significant cardiovascular benefits from using transdermal 17-beta estradiol and natural progesterone. Why weren’t these options considered, especially since the women being signed up for the study had existing heart disease? It seems that would have been a safer course of action as a first step.
There has been debate in the medical literature since the HERS trial results were published about why the early rise in heart attacks occurred, and was followed later in the study by a decline in the number of women who had heart attacks. My own hypothesis, and one that I think fits with our current science, is that the women who had early heart attacks represented the group who were more sensitive to the adverse effects of the constant daily synthetic progestin. As time went on, this more vulnerable group had been “selected out” with their heart attacks, and the remaining women may have simply been less sensitive to the adverse effects of the progestins. I also think that as time went on in the study, the beneficial effects of estrogen began to take effect, counterbalancing the negative effects of MPA, and resulting in a decrease in the number of heart attacks by the last two years of the study. One OB/GYN from Europe wrote a letter to The International Menopause Journal saying that he thought the dose of the MPA used in the HERS study was too high for women with established heart disease and was higher than he used in his practice.
What’s the “take-home” message for you? I think if you already have heart disease, or any of the risk factors I summarized earlier, you would be wise to avoid using a continuous combined horse-derived estrogen and synthetic progestin product like PremPro. If you are already on PremPro and have high blood pressure, high triglycerides, glucose intolerance or diabetes, insulin resistance, high cholesterol, or a history of heart problems, I would urge you to talk with your physician about changing to the bioidentical human forms of estradiol and progesterone to avoid increasing your risk of heart attack or stroke. I think data from a number of other well-done studies over a number of years clearly demonstrate that a nonoral (i.e., transdermal or patch) 17-beta estradiol, alone or with natural progesterone (for women with a uterus), have a much better profile of benefit on multiple cardiovascular risk factors.
I talked in chapter 6 about the role of adding testosterone for some women after menopause, particularly if they have had an abrupt hormone drop from having a surgical menopause with the ovaries removed and are experiencing marked loss of libido. I do think this important hormone has a place in the options we offer women, but it is potentially a problem if a woman has a high risk of heart disease and has abnormal levels of total cholesterol with low HDL. In such a woman, oral testosterone, or even transdermal or injections using high doses, may worsen the lipid profile by further increasing total cholesterol and decreasing the good HDL. For this reason, anyone on testosterone supplements must have regular monitoring of cholesterol, HDL, LDL, and triglyceride levels. I have not found the doses I typically use for women to cause these unwanted changes in cholesterol, but I am using lower doses than are often given to women. In controlled studies by Dr. Christopher Longcope, when testosterone was administered continuously in low doses (1.25 and 2.5 mg daily) with estrogen, there were no significant changes in cardiovascular or liver measures, including cholesterol profile.
Testosterone may also increase blood pressure, but this is also related to dose and route of administration and usually only happens at higher doses than I am suggesting. Elevated blood pressure is also more common with the more potent synthetic, chemically different forms than it is with the bio-identical, micronized “natural” testosterone I am suggesting women use. In addition, newer studies, many done in European centers, have shown that when given with the right balance of estradiol, testosterone actually helps maintain the normal mechanisms involved in vasodilatation that serve to help lower blood pressure. If given alone, testosterone and other androgens such as DHEA appear to promote buildup artery-clogging plaque (atherosclerosis) and also cause high blood pressure in women. If androgens such as testosterone or DHEA are given with estrogen, however, they have the opposite effect on the arterial wall and actually help prevent buildup of plaque in the arteries. We now have a number of controlled studies showing that low-dose testosterone therapy does not cause increased blood pressure in most women.
Transdermal patches of natural testosterone would be the most physiologically natural delivery system for restoring optimal testosterone levels for women and would avoid many of the unwanted side effects of oral testosterone, but we do not yet have such a product approved for use in women in the United States. Testosterone patches are available for men, and they work quite well. I have used those extensively in our program HIS Corner at HER Place for men who are experiencing the hormone decline of “andropause.” As a general guideline, for men or women, I think if you are taking testosterone as part of your hormone “enhancement” program, it is a good health practice to have your cholesterol, HDL, LDL, and blood pressure checked at least annually as part of your usual checkup.
In the past, medical practitioners and women have been taught that heart disease does not strike women until after menopause. Recent research, and my own clinical experience with midlife women, has shown that evaluation of ovary hormonal status may be more crucial in premenopausal women than we realized. Keep in mind that women start having increased risk for heart disease at whatever age they become menopausal based on endocrine function, not just chronological age. A woman who has either natural or surgical menopause at age forty, begins having the cholesterol and other changes that increase risk of heart disease. Those changes don’t wait to start until she reaches fifty-five. Testing for the endocrine factor allows us to identify women at risk of cardiovascular disease at a time when risk factors are reversible and when lifestyle changes possibly along with hormone therapy can make the most difference.
“Susu” is a woman I first saw for a consult when she was thirty-nine. Her story illustrates many of the points I have made about the role of estradiol and testosterone balance, PCOS, and other issues in younger women related to heart disease risk. Although she was only thirty-nine when I saw her, she had already suffered three very serious myocardial infarctions (MI) and almost died during the third one. Her first MI was at age thirty-six. Her story is quite touching, and very meaningful to me. Another patient of mine, along with a friend of Susu’s, had taken a copy of my book showing the effects of estrogen on the heart to Susu’s husband at the hospital where she was in ICU, in a coma. The doctors had told Susu’s family that it was “only a matter of time” before she died, because she wasn’t responding to the medications they customarily used for acute MI. Because Susu’s friend knew that Susu’s heart attacks had always come during her menstrual periods when estrogen is lowest, the two women and Susu’s husband shared my chapter on estrogen and the heart with Susu’s cardiologist, asking that he consider trying an estradiol patch for Susu. The cardiologist read the material I had summarized about estradiol’s many positive effects on heart function and said, “Nothing else is working, we may as well try it.” To everyone’s amazement, including the doctor’s, Susu began recovering. Her “ejection fraction” that had been at critically low values, began increasing within hours of having the Climara patch applied. Slowly she began coming out of the woods and was able to be discharged home.
She had written me about her story at the time she scheduled her first consult, and I was myself overcome with emotion when I read this letter and found that my writing had such a profound impact on a young woman’s life. When she was well enough to travel and come to our Texas office, I was amazed at all of the progress she had made since her near-death experience. I was able to review her serum hormone levels with her and show her why the estradiol patch had helped so much: Her own menstrual Day 1 estradiol was barely detectable, and her free and total testosterone and DHEA were all quite high, as were her total and LDL cholesterol, triglycerides, and insulin. After a careful evaluation by our gynecologist and me, we were certain she had PCOS as the underlying cause of her cardiovascular disease. It is now three years later, and she is doing well as a more active mom able to be involved with her children and her life again. She is on hormones designed to keep her as steady as possible, lower the androgens, and prevent the falls in estradiol that triggered the severe coronary artery spasms leading to her heart attacks. She has made marked changes in her diet and is following a plan designed to minimize insulin resistance, which has helped her lose the excess weight gradually. And, she is now able to engage in a regular walking program to rebuild her strength and stamina, as well as further improve the insulin resistance. With her involvement in the Internet support groups for PCOS, she has become an avid spokesperson to help other women understand this disorder and get proper evaluation of these hormone issues.
So in summary, I encourage all women, and their physicians, to take into account the premenopausal hormone changes, which can be readily checked as part of an overall approach to your health care for women. If you think you are beginning menopause (regardless of how old you are), or if you have a condition like PCOS that causes excess production of androgens and increases your risk of heart disease, and you have a significant family history of heart disease, it is important to ask your physicians to do a simple blood test of FSH and estradiol on Day 1 or 2 of your menstrual bleeding, along with the usual metabolic chemistry panel and cholesterol profile (make sure it includes HDL). This can help identify possible premenopausal changes adding to your cardiovascular disease risk.
If you already have high cholesterol and/or high blood pressure, it is even more important to ask your physician to check your hormone levels so that this can be considered in your therapy. We have good screening and treatment techniques now available for reproductive cancers, so it is crucial that you also understand and address the greater risks of disability and premature death from osteoporosis, heart disease, and strokes, which increase as estrogen declines. Today’s studies are clear that women still seriously underestimate their risk of heart disease—most women are off by a factor of thirty-fold in their perception of risk of breast cancer compared to their risk of heart disease. If you do not perceive your risk accurately, then you will not take the steps to prevent a problem, so it is crucial for you to have an accurate picture of your individual health risks.
I have found it can be very rewarding as a physician to explain these midlife endocrine changes and their effects on blood pressure, lipid profile, palpitations, and overall risk of heart disease. My women patients have been interested and even excited to learn about these connections and have been even more motivated, by the knowledge, to incorporate needed dietary and exercise approaches and to consider whatever hormonal therapy may be desired or appropriate. It also adds to your own sense of taking control of your health by exploring your many options after having a medical assessment that focuses on what makes your body different from a man’s.