The Women's Health Initiative (WHI) is the largest study to date on the risks versus the benefits of hormone replacement therapy (HRT). It was stopped three years early on July 9, 2002. This made headlines across the world because the study was stopped early due to the belief that the risks of HRT outweighed the benefits. Many studies have been done looking at the risk/benefit ratio of hormone replacement therapy, but most of these studies were smaller observational studies. The WHI involved 27,000 women in multiple cities, which was sponsored by the National Institute of Health (NIH). This study was a randomized, doubly blind study. The patients were randomized to hormones or a placebo (sugar pill) and neither the patient nor the doctor knew which arm of the study they were on. This is the gold standard when looking at research. The purpose of the study was to assess the long-term risk/benefit ratio of HRT in disease prevention. The study evaluated the incidence of heart disease, strokes, breast cancer, osteoporosis, and colon caner. The study was supposed to last eight years until 2005.
Two different studies were undertaken. 16,608 women without a hysterectomy were in the study involving Premarin/medroxyprogesterone acetate (Prempro), which was the study that was stopped in July, 2002. Per 10,000 women per year taking Prepro instead of a placebo they saw 8 more cases of breast cancer, 8 more strokes, 8 more incidents of pulmonary embolism, 7 more heart attacks, 6 fewer cases of colon cancer, and 5 fewer hip fractures. Only 2.5% of the women on Prempro had these adverse health problems. Even the authors of the WHI stressed that this increased risk should not be a cause for major alarm.
This study has many faults. First of all quality of life was never evaluated. Ever since the results of this study were published, millions of women have gone off of their HRT. After stopping their hormones, many women are suffering, and are fearful to go back to taking hormones. If a study concludes that the relative risk of a drug is only slightly elevated, the difference in quality of life must be evaluated.
There have been multiple observational studies prior to the WHI with no conclusive evidence that estrogen replacement therapy increases the risk of breast cancer. The relative risk for developing breast cancer on Prempro in the WHI study was 1.26. A relative risk of 1.0 is considered of no risk and many doctors do not consider a drug to be a risk until the number reaches 2.0. In contrast, the relative risk of developing lung cancer from smoking is 29.0. There are also numerous other risks for breast cancer that are greater than taking Prempro; night shift work (RR 1.36), not having children (RR 1.40), left handedness (RR 1.42), having your first pregnancy after 29 years old (RR 1.48), obesity (RR 1.60), an average of two alcoholic drinks a night (RR 1.7), greater than 13 years of education (RR 1.79).
Most women are convinced that taking HRT is going to cause them to develop breast cancer. It takes approximately seven years to diagnose breast cancer once it develops, so we cannot say that Prempro causes breast cancer because these women were only evaluated for five years. It raises the question that perhaps Prempro promoted the growth of pre-existing breast cancers. Many breast cancers have estrogen and progesterone receptors, so taking HRT will make a lot of these cancers grow more rapidly and thus they are diagnosed earlier.
Though this study was short lived, the Provera in Prempro has been shown to increase the risk of breast cancer in earlier studies. Studies looking at estrogen versus estrogen and Provera show an increase incidence of breast caner in the latter. Studies have shown no increased risk when natural progesterone is added to estrogen. Additionally, it is felt that Provera may provide insufficient balance for estrogen, making a woman estrogen dominant, causing an increase in breast cancer. The WHI found a decreased incidence of breast cancer in the group taking Premarin without Provera, though it was not statistically significant.
Seeing an increased incidence of heart disease was very distressing, because physicians have been giving HRT to women for years, telling them that it was good for their hearts. This was not surprising for the practitioners who have looked at the previous studies involving Provera. Provera is a synthetic progestin, not progesterone or even close to it. Provera attenuates the benefits of estrogen. Provera raises LDL and total cholesterol, and lowers HDL cholesterol. As a result, it is damaging to the vascular system. A study published in the Journal of Reproductive Medicine showed that progesterone did not negatively affect estrogen's positive effect on the heart, whereas Provera did. In another study progesterone, but not Provera, enhanced the beneficial effect of estrogen on exercise induced myocardial ischemia (lack of oxygen to the heart). In several other studies, Provera was shown to constrict coronary arteries, causing vasospasm and myocardial infarction (heart attack), whereas progesterone dilated coronary vessels in primates. It is felt that natural progesterone has a direct impact on reducing platelet aggregation through its ability to enhance endothelium-derived nitric oxide. Progesterone also increases HDL cholesterol, making it even more protective to the heart.
The Heart and Estrogen/Progestin Replacement Study (HERS) study was published in 1998. Previous studies like the PEPI study and the Nurses' Health Study suggested that HRT may provide cardio-protective benefits in women without coronary artery disease. The HERS study evaluated whether or not Prempro could prevent myocardial infarction in postmenopausal women with established heart disease. They saw an increased incidence of myocardial infarction in the first year of Prempro, but then a protective effect in years 2-4. They found similar findings in the WHI; the major risk was in the first year of treatment. The data from these studies demonstrate that progesterone has a different effect on the body compared to Provera. Critics of this philosophy state that because both progesterone and Provera act on the same receptors, they should elicit the same response. These molecules are different from one another structurally and thus elicit different responses.
It was stated that the women in the WHI study were healthy. However, their average body mass index was 28.5, which is equivalent to 5'6”, 180 pounds . Fifty percent of the participants had a history of smoking, thirty-five percent had hypertension, 4.5% had diabetes, and 2% had a history of a heart attack. The biggest problem with the study was the average age of the women was 63, and only one third of the participants were in their fifties.
Only 25% of the women had a history of HRT use. We have known for a long time that the vasculature loses its estrogen receptors once artherosclerosis sets in. As a result, women no longer benefit as much from a cardio-protective standpoint when given estrogen at this time. It is also presumed that women start developing cardiovascular disease rapidly after menopause without the protectiveness of estrogen. Estrogens and especially medroxyprogesterone acetate (Provera) can cause embolisms in artherosclerotic arteries. An embolism is when a plaque in an artery dislodges and travels elsewhere. If an embolism occurs in the coronary arteries, it causes a heart attack. If an embolism occurs in the carotid arteries, it causes a stroke. This is why an increase in heart attacks was seen in the WHI and the HERS studies, especially in the first year of use. The HERS study was similar to the WHI in that these women started taking Prempro many years after menopause, after artherosclerosis had set in.
HRT should be started at menopause, not at age 63. To support this theory we should look at the studies involving birth control pills. Birth control pills (OCPs) have very large dosages of synthetic hormones, much larger than HRT. When perimenopausal women are given oral contraceptive pills (OCPs) there is no increase in heart disease or breast cancer. OCPs have actually been shown to decrease the risk of cardiovascular disease. The reason for this is that these women have not gone for a significant period without estrogen in their bodies.
Women in the WHI study with a previous hysterectomy were either given Premarin or a placebo. This study was halted in March 2004 because it was felt that Premarin did not have benefits over a placebo. It was determined that there was no increase or decrease in heart disease or breast cancer. Though there was a 9% reduction in heart attacks and a 23% reduction in breast cancers in women on Premarin; these numbers were not statistically significant. There were significantly fewer colon cancers and cases of osteoporosis in women on Premarin. There was a statistically significant increase in strokes in women on Premarin. This again can be attributed to unhealthy women being given estrogen after many years of not having its protectiveness. There was not an increase in strokes in women in their fifties on Premarin.
Of the forty observational studies evaluating estrogen and cardiovascular disease, almost every one has shown that estrogen has a protective effect. We cannot dismiss what we know about hormones based on one study. Estrogen decreases total cholesterol, increases HDL, and decreases LDL. It does raise triglyceride levels. It also lowers lipoprotein (a), homocysteine, and C-reactive protein (CRP) levels, giving additional cardiovascular benefits. Estrogen also has direct vascular effects. It increases vascular dilatation by relaxing the smooth muscle cells within the vessel wall. Estrogen increases endothelial cell growth, increases insulin sensitivity, and decreases coagulation factors. It also decreases uptake of LDL in the coronary arteries. This results in a decrease in artherosclerosis and overall protection to the coronary arteries. It's no wonder that heart disease is much less common in women prior to menopause before estrogen levels decline dramatically.
Prempro and Premarin were used in the WHI study because they are the most widely used of all HRT. Although Premarin is not as harmful as Provera, it is still consists of foreign substances. Its name originates from PREgnant MARes urINe. It consists of 30 different equine estrogens and all except one are foreign to the human body. The only hormone that resembles a human hormone is estrone. Premarin is three times more potent than your own hormones and can exist in the body for more than six weeks after taking it. A study showed that one ingredient, 4-hydroxy equinlenin, causes single-strand breaks in DNA and oxidation of DNA bases. It is well known that damage to DNA can lead to cancers, such as breast cancer.
It is hard to believe that a woman would take potentially harmful synthetic or foreign hormones when she can take the exact replica of the hormones she produced her entire life. Pharmaceutical companies will not produce bioidentical hormones because they cannot patent them. But they can develop a synthetic hormone, patent it, market it, convince physicians to use it, and then make a lot of money. They then donate their drugs to be used in studies. The major limitation to the WHI was that it only evaluated two forms of HRT, Prempro and Premarin. Obviously larger studies need to be performed using bioidentical hormones. We would see much different results; it does not make sense for these hormones to be protective to a woman in her 40's but not in her 50's.
Another problem with the study is that it did not evaluate different routes of administration, such as transdermal application. It is shameful that all forms of hormones are grouped together as HRT as if they are all the same medication. I wish headlines would state “Prempro is bad for you” instead of stating “HRT is bad for you”. People need to understand that women are healthiest when their hormone levels are at their prime. It is not until hormones start declining and synthetic hormones are added that we start to see health problems. Instead of discontinuing Prempro, Wyeth pharmaceuticals recently introduced a lower dose of Prempro.