Hormones and a Woman's Heart

With the early termination of the Women’s Health Initiative (WHI) Trial of a fixed combination of estrogen and progestin on the health of post-menopausal women, we are faced with more questions than answers regarding the true impact of post-menopausal hormones in women.

In order to apply these published results to your own health or the health of those you care for, each woman should find out whether the women in the study reflect her own personal situation. To help you understand what this study showed and what it did NOT show, information is provided in the form of questions and answers. 

Who was in the WHI study?

Starting in 1993, 16,608 post-menopausal women were enrolled in WHI. Participants were between the ages of 50 and 79 years and had an intact uterus. They were recruited from 40 centers across the U.S. Most of the women (74%) had never been on post-menopausal hormones and only 6% were currently using post-menopausal hormones when they enrolled. The average woman participant was about 15 years post-menopausal and not on hormone replacement when enrolled in the study.

What was WHI designed to study?

WHI was designed to study the impact of combined estrogen plus progestin on healthy post-menopausal women. Women were randomized to receive placebo (8,102 women) or combination hormone replacement therapy (HRT) of Premarin 0.625 mg plus Provera 2.5 mg a day (8,506 women). Their health problems were followed and the main outcome of coronary heart disease (CHD) including nonfatal heart attack or CHD death was noted. Invasive breast cancer was tracked as an adverse outcome and a global index was calculated, balancing risks and benefits including CHD, invasive breast cancer as well as stroke, blood clots to the lung, endometrial cancer, colon cancer, hip fracture and overall death due to other causes. The planned trial was to last 8.5 years.

Why was this trial done?

While post-menopausal hormone replacement is used for the symptoms of estrogen deficiency (hot flushes, cold and heat intolerance, sleep disturbances, mood swings, and emotional upsets) and prevention of osteoporosis that women may suffer around the time of menopause, it is not known what impact it has on chronic diseases that women face as they age. Estrogen is replaced in women without a uterus, but progesterone is replaced as well to prevent the development of endometrial cancer in women with a uterus. There are many formulations of estrogen and progesterone (progestin is the term used for artificial progesterone). The combination of conjugated equine estrogen (Premarin) and medroxyprogesterone acetate (Provera) was used as this is the most widely used combination.

Estrogen is known to have a beneficial impact on blood vessel function and lipid levels. Dozens of population-based studies have consistently shown a lower rate of heart attacks and cardiac death in women who are on post-menopausal hormone therapy. A higher rate of blood clots in the legs and to the lungs has consistently been found However, since the women in these population-based trials had decided on their own to take hormones, doctors could not separate out a beneficial effect of hormones on heart disease from a decision of healthier women to take hormones. By randomizing treatment based upon a woman’s age and other pre-determined risk factors in WHI, researchers hoped to discover the effect HRT had on coronary heart disease for all women.

Similarly, while estrogen and progestin are known to have an impact on the growth of breast cancer in laboratory situations, an analysis of published trials has shown a great variation in the rates of breast cancer in women on various HRT and estrogen regimens. Risk factors for breast cancer have included family history of breast cancer, early age of menarche (the start of menstrual periods), later menopause (the cessation of menstrual periods), birth of first child after age 30, less breast feeding, and age. Recent studies showed minimal breast cancer increases on estrogen alone, slightly more on estrogen and continuous low dose progestin, while a significantly higher rate was seen with the use of cyclical higher dose progestins. The impact of hormone therapy regardless of type had been found to be less than several other risk factors, such as having a first child after age 30. In spite of these issues, most trials showed no increase in breast cancer when women were on hormones for less than 5 years, with a modest increase in rates with longer use as well as with higher dosages, especially of progestins. Since it takes 16 to 20 years for breast cancer cells to develop into a cancer that can be diagnosed, it has not been clear if the use of HRT causes breast cancer to grow more quickly and be discovered earlier, or if it causes breast cancer to develop in a woman that would not have had it otherwise. By identifying known breast cancer risks and following women for many years, researchers in WHI hoped to discover the effect the lower dose continuous progestin and the estrogen in this HRT regimen has on breast cancer for all women.

What were the principal results of WHI?

After 5.2 years of study, the researchers found that women on HRT had more heart attacks, strokes, invasive breast cancer and blood clots to the lungs than the women not on hormone therapy. Researchers also found that women on HRT had less colon cancer, endometrial cancer, hip fractures, death due to other causes and slightly less total deaths.

Why was WHI stopped early?

The monitoring board found that the overall measured health risks were not outweighed by the overall measured health benefits and did not justify the intervention of medication for primary prevention of chronic diseases.

Was this information new or unexpected?

Not really. The development of blood clots in the legs and lungs accounts for the greatest number of additional events in the women on HRT. This is a well described risk of HRT and is found in other situations where female hormone levels are elevated or used, such as during pregnancy or the use of birth control pills.

With regard to CHD events, the 1998 HERS trial studied postmenopausal women with a mean age of 67 years with known coronary heart disease on the same HRT as in WHI, compared to placebo. This study showed an early increase but a later drop giving an overall equal rate of cardiac events over 5 and 6+ years in women with heart disease on HRT compared to placebo. While HERS followed fewer women, their risk of heart attack or cardiac death was higher than in WHI because they had established coronary heart disease. There was an expected increased risk of blood clots. No increased risk of breast cancer was noted in the study over 6+ years. Analysis of various subgroups of women in this study found that there was NO significant early increased risk of cardiac events in the women on HRT who were treated with statin medication, the powerful cholesterol lowering medication used in many people to reduce their cardiac risk. This study was planned as a secondary prevention study, to see if HRT would prevent the recurrence of cardiac disease and events with women with known heart disease.

The WHI study showed a similar but less pronounced increased risk in CHD events in the first year in the women on HRT compared to placebo. In subsequent years, there was a decreasing risk of cardiac events so that by year 4, the risk was equal. In year 5, there was a dramatic decrease in risk in the placebo group (that has not been explained) while the actual number in the HRT group continued to decrease. In years 6 and later, the risk of CHD events was lower in the HRT group than in the placebo group. As the trend with time was for decreasing for CHD events on continued HRT in WHI, it is unfortunate that the monitors did not feel that the benefits of following this trend were important enough and/or worth the potential risks to follow.

With respect to breast cancer risk, an increased rate was noted in other large studies of breast cancer and HRT (Ross RK et al in JNCI2000 and Schairer C et al in JAMA 2000) corresponding to a rate similar to that found in WHI. The increase rate in WHI was almost, but not quite, of statistical significance for the women on HRT in the study and occurred earlier in time (by year 4) than seen in other studies. However, when only women who had NEVER USE HRT PREVIOUSLY were evaluated, there was NO SIGNIFICANT DIFFERENCE in breast cancer compared to placebo. This indicates that the prior use of HRT significantly impacted the study results and needs to be taken into account in recommendations as well as further evaluated. 

Does this mean I should not use hormones?

No, but it does mean women should think about their reasons for using hormones as well as their risks and concerns. This study was NOT designed to measure or take into account the reasons women already use HRT – for symptoms of estrogen deficiency. However, it does make us look more closely at the women that were studied and the results they found on the impact of HRT on their risk of chronic diseases such as blood clots in the legs or lungs, coronary heart disease, or on their risk of breast cancer.

Even though the risks were higher for some of these conditions for women on HRT compared to placebo (most notably, for blood clots in the legs and lungs), there were trends for decreasing heart disease with continued use and confounding issues on the breast cancer risk. While the increased breast cancer risk over the study was ALMOST of statistical significance for all the women on HRT, the breast cancer risk was NOT significantly higher for the women who had NOT been on hormones previously. Since we were not given the information about the regimens taken by the women who had been on hormones previously, we cannot compare their situations. Many other cancers had lower risks on HRT and overall mortality was slight lower on HRT, but not significantly. We recommend that women make a decision to use or not use hormones based on proven benefits for symptoms, their personal experience, and discuss or address other issues with their physicians every 5 years or if their health condition changes.

Why should we look more closely at the women that were studied? Aren’t they just like me?

The only woman just like you is you. That is why the decision to use hormones or not has to be individualized. The women in WHI were NOT like the usual American woman who decides to use hormones for menopausal symptoms. Most women enrolled in WHI were many (>5) years into menopause and did NOT have menopausal symptoms: 33% were 50 to 59 years, 45% were 60 to 69 years, and 22 % were 70 to 79 years.  Almost three out of four of the women had never used hormones, only 6% were using hormones at the start of the trial.

Most American women who start HRT do so for symptoms early in menopause and continue therapy for a variable number of years. These women have not been estrogen deficient for any significant period of time. Laboratory studies have shown that the effect of estrogens on blood vessels continually exposed to estrogen is much more protective against heart disease than the effect of estrogens on bloods vessels that have been estrogen deficient for some time. In order to see if this laboratory effect corresponds to a lower CHD event rate, women would have to be enrolled in a WHI-like study as they entered menopause rather than enrolling them up to 30 years after being without estrogens post-menopause. However, the low number of cardiac events in women in their late forties and early fifties means that a large number of participants would have to be followed for many years in order to obtain enough incidents of heart disease to have the results of such a study reach statistical significance. A glimpse of this type of study could be seen by looking at the subset of the participants in WHI, the women who were enrolled within a year of menopause. If the cardiac events, breast cancer diagnoses, fractures, blood clots and strokes in these women were evaluated and followed for several more years, we could learn whether HRT given at the time and for the reasons most women use it truly impacts the occurrence of chronic diseases.

We have not seen any specific information about the role of estrogen use alone or with a progestin on breast cancer rates based upon whether a woman has been post-menopausal for some time before starting HRT. That type of detailed information could be very useful in interpreting results of trials such as WHI.

Was there a difference in the women in WHI who were on hormones before the study began?

So far, we only have the subgroup data that was included in this first article. This data showed NO significant difference in the risk of breast cancer in women that were NOT on hormones prior to the study, whether they were on HRT or placebo for the trial. I repeat, when only the women who had never been on hormones were looked at, there was no significant difference in breast cancer diagnosis. The actual difference in breast cancer rates between the HRT and placebo group (still, slightly higher for the HRT group) was so small that other variations in risk, such as the difference in family history of breast cancer, age at menopause, or absolute age could make a difference. 

However, if the women were on hormones before the study, their risk of breast cancer was significantly higher for those on hormones for less than 5 years before the study (giving them 5 to 10 years overall) and for those on hormones for 5 to 10 years prior (giving them 10 to 15 years of hormone use overall.) There was an increase that was not statistically significant for women on hormones for more than 10 years at any time before the trial began. This raises the issue of whether breast cancer is diagnosed sooner in women on HRT, possibly because of increased tumor growth after several years of use, and begs the question as to whether the actual number of breast cancers is any different in any study that is continued long enough.

We were NOT given prior hormone use data breakdown for CHD events.

Did the article separate out results of the breast cancer rate in the women based upon their age and breast cancer risk factors?

No, the study did not report breast cancer data results based upon patient age, their age at menopause or their individual pre-study breast cancer risk factors. BRCA gene results were not reported in this article and patients were not randomized based upon the results. Gail model 5-year risk of breast cancer was calculated at baseline and there was a 0.5% greater number of women on placebo in the lowest risk group, but this was not felt to be significant. The authors did not find any interaction between HRT and Gail model 5-year risk scores.

What about the use of soy products? Was that taken into account in the study?

No information was given in the published article to suggest that long term soy intake, other dietary factors, nutritional supplements or other supplements were identified or randomized for. Population studies have shown that women who eat diets life-long that are high in soy products have a lower incidence of breast cancer as well as less menopausal symptoms. The use of soy products has also been shown to help prevent heart disease. If dietary information was obtained, it may be reported in further articles.

If I am worried about heart disease, what should I do?

You should speak with your physician about your cardiac concerns, find out what your risk factors are, evaluate any symptoms to find out if you have evidence of obstructive coronary disease now, and learn what should be done about your risk. We have excellent information about the benefits of healthy lifestyle (healthy diet, exercise, weight), statin therapy, smoking cessation, the use of aspirin for women with risk factors for heart disease and the benefits of treatment for cardiac risk factors including high blood pressure and diabetes.

The subgroup analysis of patients in the HERS trial showed a dramatic reduction in blood clots in the legs and lungs as well as in CHD events for women on statin therapy, whether they used HRT or not. Any woman considering HRT for symptoms should consider statin therapy as well, as this treatment may reduce the risk of blood clots and CHD events to below the risk on placebo.

What about the benefits of estrogen on blood vessel function? Doesn’t it really help?

Research has shown that estrogen definitely maintains healthy blood vessels and their function. However, we do not have any evidence to show that giving estrogen back to women who have been estrogen deficient for many years will restore all the benefits that estrogen can provide to blood vessels when it is used continuously. WHI did not study women who were on HRT continuously. HRT was given to most participants who were 10 to 20 years after menopause. WHI did not measure blood vessel function or report results of cardiac events based upon whether women were current or past hormone users compared to new users.

If estrogen helps keep blood vessels healthy, why did women on HRT have more CHD events?

We know that acute cardiac events such as a heart attack usually occur when a coronary blood vessel plaque becomes unstable and its surface cracks or ruptures, forming a blood clot over the plaque. If a woman’s balance of blood clotting is low or less likely to clot, she will form little or no clot and not obstruct her blood vessel flow. She may have no symptoms from this event and heal her blood vessel without ever knowing that a rupture or crack occurred. On the other hand, if a woman’s balance of blood clotting is high or more likely to clot, she will form a large clot that could obstruct her blood vessel flow. She will be likely to have heart muscle damage causing a fatal or nonfatal heart attack. We know that estrogen increases blood clotting through some factors while it decreases blood clotting through other factors, so in balance, its impact on clotting in most women is even. However, in women with certain types of blood clotting genetic (inherited) mutations, estrogen will significant increase their blood clotting, more so in the veins (such as blood clots in the legs or going to the lungs) and less often in the arteries, such as in the heart or brain. This is the major reason found for the more frequent occurrence of blood clots in women on birth control pills or during pregnancy. In WHI, the women with these blood clotting mutations may have increased their likelihood of having blood clots in their legs or to their lungs, as well as increased their likelihood of CHD events because of the increased clotting interaction of their mutations with HRT. Other as yet undiscovered effects of HRT may also have played a role in the adverse effects. Only by looking at differences between the women who had events and the women who didn’t will these types of differences ever be found.

Are these kinds of genetic mutations common enough to have impacted the results of WHI?

Absolutely. We know that the most common genetic mutation impacted by estrogen, Factor V Leiden, occurs in about 6% of Caucasians, 4% of African-Americans and Hispanics, and virtually never in women of Asian descent. Prothrombin 20210 mutations occur less often, in up to 2% of women. Blood clots in the legs and to the lungs are seen significantly more often in women with these mutations, especially in those who are on hormone replacement, birth control pills or during pregnancy. This is one of the reasons why blood clots have been a known adverse side effect of birth control pills and HRT.

Cardiac events such as fatal or nonfatal heart attacks occur more often in women with these mutations who are on hormones as well. The increase in events appears to interact with other cardiac risk factors such as high blood pressure or elevated lipids. In a study of women with elevated lipids, compared to women with normal clotting not on estrogen (ERT-), those on estrogen (ERT+) with Factor V Leiden mutations (Factor V+) were 2.4 times more likely to have an acute cardiac event. Women with normal Factor V (Factor V-) on estrogen (ERT+) were less likely (0.4 times) to have an acute cardiac event. Even more dramatically, in a study of women with hypertension, those on HRT (HRT+) with Prothrombin 20210 mutation (20210+) were 10.6 times more likely to have an acute cardiac event, compared to women on HRT that had normal Prothrombin 20210 (20210-). These mutations can be screened for with a simple blood test and only need to be done once. The impact of these mutations appears to be related to the presence of other cardiac risk factors and how well controlled those risk factors are, so just having the blood clotting mutations is not the whole story. Some doctors recommend doing these tests before starting a woman on birth control pills or hormone replacement, as well other tests for cardiac risk factors.

Were these clotting mutations tested for in WHI?

Factor V Leiden and Prothrombin 20210 tests were not included as part of the randomization of the women in WHI, however, these and other genetic tests may have been done on the women in the study. The outcome results should have been reported based upon these common genetic mutations for any adverse event associated with blood clotting, such as coronary events, blood clots to the legs or lungs, and strokes. Since we know and have other smaller studies showing that these mutations interact with cardiac risk factors, the evaluation of events needs to include the interaction with cardiac risk factors as well. (See attached graphs.)

Can this information be obtained?

Subgroup analysis will be reported in future years on events in WHI. We hope to have the impact of genetic mutations included in these analyses. If this is done, we may see if the role of HRT on adverse events such as breast cancer, heart attack, blood clots or stroke can be determined in specific women by genetic testing BEFORE starting hormones. If we can identify a small group of women who should NOT be on HRT, we may be able to better understand the true risks and benefits on chronic diseases on women with normal genetic tests who desire the benefits of HRT for symptoms.

Where can I learn more about this?

Speak with your doctor. Only your doctor can help you balance your symptoms, risk factors and risk-benefits to determine what is most important for your health.

©Copyright 2002 Debra R Judelson MD

 

logobutton Return to home page

Last updated on October 17, 2002.