The Women's Health Initiative (WHI) was a large, randomized preventive clinical trial which was initiated in 1991 and funded by the federal government to determine if hormones prevent heart disease, breast and colorectal cancer and osteoporotic fractures in postmenopausal women. The trial involved women who used Premarin (estrogen derived from Pregnant Mare's Urine) and Provera (medroxyprogesterone acetate which is a synthetic, non-bio-identical progesterone called a progestin) each day. This was one of the most commonly prescribed hormone therapies at the time in the United States among women who still had a uterus.
There was also an estrogen-only group for women who did not have a uterus, a placebo (sugar pill) group, and a lifestyle and diet group. In its entirety, the WHI enrolled over 161,808 postmenopausal women between the ages of 50-79, with the majority of the women being 60-69 years old in the group and the average age of 63 using the hormone therapy. Prior to this study, most trials had been on men with study results being extrapolated to women. The Woman’s Health Initiative was initiated in1991 and launched in 1993 by the National Institutes of Health (NIH). This landmark study was the largest ever United States Women's Health Prevention study of its kind with an initial budget of $625,000,000.
What are the main findings in the study on Premarin plus Provera?
When compared to women taking a placebo, the study showed:
What are the conclusions from these findings?
Confusion and Lingering Fears about Hormones Replacement Therapy from the WHI
On July 9, 2002, the Women’s Health Initiative (WHI) was abruptly halted several years early due to several unacceptable risks that had surfaced. I distinctly remember the day in my office when the report became public. Our phones were ringing off the hook and millions of concerned women exposed to the media frenzy abruptly stopped taking their hormone therapies cold turkey on the advice of their physician and on their own. This is when I and many other physicians began to rethink hormone replacement therapy and to look for other options for relief. Much time and effort has been spent on reevaluating the results of the WHI Study. Despite questions raised about the validity of the WHI Study, I believe the study itself provides grounds for caution since the use of synthetic estrogen and progestin replacement appears questionable at best.
I can certainly understand the fear created by the findings from this landmark study but there were many flaws in the study. The WHI study was probably the biggest medical news of that year. The media played up the doom and gloom for all the increased attention and readership they could get from the story. Wyeth, the maker of Prempro, wasn’t too happy either as their stock dropped more than a third of its value soon after the story hit the papers. But how could a drug be so wonderful one day and so horrible the next? The truth is probably somewhere in the middle. As the hype and hysteria raged on over the Prempro arm of the study, another arm of the study using estrogen-only continued and the result would be quite different.
This arm of the WHI-2 study involving estrogen-only continued despite the abrupt halt of the WHI-1 Prempro study arm. The Premarin-only arm involved 10,000 women who were given only estrogen because they did not have a uterus and therefore were not at risk for uterine cancer. Corroborating some previous forty other studies on estrogen-only; the WHI-2 study found no increased incidence of breast cancer and even revealed a 21% decrease in the incidence of breast cancer over the group taking no hormone at all during the 13 year follow-up. No increase in heart attacks or strokes with estrogen-only were found, but consistent with almost all other studies on oral estrogens, there is a significant increase in the incidence of deep vein thrombophlebitis.
Flaw #1. Non-Bio-identical Hormones
The hormone replacement therapy (HRT) used was a combination of conjugated equine estrogens (Premarin) derived from the urine of pregnant horses which also contained multiple other horse estrogen hormone components (Equilin) foreign to the human body plus medroxyprogesterone acetate (Provera), a synthetic and non-bio-identical progesterone. Since natural hormones work like a lock and key with the human hormone cell receptors, using non-bio-identical hormones instead of the identical versions is like trying to unlock a door lock with a key that doesn’t quite fit. It may partially work sometimes and not others and may even cause harm to the lock. I believe that is the reason there are many unintended consequences and adverse reactions with synthetic hormones. Failing to include natural, Bio-identical Hormones in the study was a major mistake. Having done so would have provided a much clearer and more definitive comparison between synthetic versus natural hormones, and in my opinion would have reduced or eliminated the fear and confusion that is still prevalent today.
Flaw #2. Oral Estrogens Promote Clotting Factors
All hormones taken by mouth increase the risk of blood clots, heart attacks, and strokes where increased vascular clotting is involved. Once swallowed, oral estrogens are broken down in the digestive tract and absorbed. After absorption, estrogens are transported to the liver where it is detoxified and metabolized into components that increase clotting and inflammation which are believed to be factors that increase the cardiovascular risks. Estrogen that is not taken orally and is absorbed through the skin or subcutaneous tissue do not increase the risks of clot formation and therefore are not associated with these risks.
Delivery of natural, bio-identical hormones through or beneath the skin bypasses the liver, just as the body’s own glands secrete natural hormones into the blood stream that travel directly to hormone receptors of virtually every cell in the body without first having to pass through the liver which eliminates the risk for clotting and inflammation.
Flaw #3. Natural Progesterone vs Progestins
Progestin, the synthetic version that is found in Prempro, significantly increases cardiovascular risks and the risk of breast cancer. Progesterone, the hormone that is naturally made in the body and available in bio-identical hormone replacement therapy, does not increase the risk of either cardiovascular or breast cancer risk and some studies show that it may even decrease the risk of both.
The differences of behavior of various hormonal formulations are directly connected to the differences in molecular structure as described in the scientific literature. As early as 1980 and continuing into the present scientific literature, the adverse side effects of synthetic non-bio-identical progestins such as increased blood clots, overstimulation of breast tissue causing cancer, cardiovascular, cholesterol, carbohydrate, and lipid metabolism disorders have prompted more research into natural progesterone as a safer option.
If all of these studies point to natural estrogen and progesterone as a much safer and more effective option, why then would drug companies develop these synthetic versions to use in their products? Sadly, the answer lies in the fact that, by law, natural hormones are not able to be patented, and therefore the huge revenue profits they now receive by developing synthetic, proprietary versions would not be possible.
While further long-term randomized trials would be helpful to quantify the difference of the efficacy and safety between synthetic and bio-identical hormone replacement over the long term, the current state of evidence demonstrates bio-identical hormones to be a safe and effective option to promote health, wellness, and well-being.
Flaw # 4. The Beginning Age of Treatment was late
The average age of the women who were enrolled in the WHI Study was sixty-three. Most of these women had been menopausal for ten or more years and had not enjoyed any of the potential health benefits of hormone replacement. Many vascular and silent inflammatory changes, rising blood lipids, and thickened blood vessels had already progressed between menopause and starting the HRT that was begun with the WHI Study.
Many physicians have noted the relative immunity to cardiovascular, breast disease, osteoporosis and many other debilitating diseases that younger women have enjoyed in their youth as opposed to their male counterparts. However, many physicians have also noted that after menopause, many women catch up with men in the frequency of these diseases.
Follow-up evaluation data after the women's health initiative was halted has continued to yield valuable information. Timing of treatment appears to be critical when looking to improve the benefit-to-risk ratio. For women younger than 60 or for women who began treatment with natural, bioidentical hormone replacement therapy initiated less than 10 years after transition into menopause, study results clearly show that they enjoy significant benefit with minimal risk. However, the case is less clear for older women who failed to begin treatment within 10 years, although this does not mean they should never be considered for hormone replacement therapy.
According to the North American Menopause Society, hormone replacement therapy still remains the most effective treatment for hot flashes, vaginal dryness, and other adverse events associated with menopause.The most reasonable conclusion after evaluating hundreds of detailed articles and studies is that bio-identical hormone replacement therapy used appropriately can help women stay young longer, age gracefully, and avoid many of the debilitating, degenerative, and deadly diseases associated with menopause.