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 Interview with Dr. Isaac Schiff, Joe Vincent Meigs Professor of Gynecology at Harvard Medical School and Chief of the Vincent Obstetrics and Gynecology Service at the Massachusetts General Hospital.
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DR. SCHIFF: The major reason for taking the two hormones together every day of the month, or what is known as continuous combined therapy, is to avoid having a period. So, instead of thinking of continuous combined therapy as duplicating natural hormones' functions, the best way to think of it is as a therapy to relieve symptoms.
When a woman makes estrogen for two weeks and then estrogen along with progesterone for the next two weeks, the lining of the uterus undergoes various changes, from proliferation initially, to more glandular formation when the progesterone is made. This prepares the lining of the uterus for a fertilized egg. If the woman does not conceive, the two hormone levels decline and the lining of the uterus comes out in the form of a period. It was theorized that if one tries to mimic pregnancy, namely, when the body is making lots of estrogen and progesterone and in that case the lining of the uterus does not grow.
Thus, in the pseudo-pregnancy state, it was thought that endometriosis, where the normal lining of the uterus is outside its traditional site, would atrophy and shrink, and that similarly, the lining of the uterus would not undergo stimulation and thus there would not be monthly periods. This is the thrust behind using estrogen and progesterone together. It was first done with the birth control pill when the two were used together and then taken every day of the month instead of stopping.
CBS CARES: So, if a woman takes hormones the way her ovaries used to produce them, by taking estrogen the first two weeks of her cycle, and then estrogen along with progesterone the last two weeks, she will have a period again?
DR. SCHIFF: Right, she will experience monthly withdrawal bleeding even though her body has no more eggs left and she can't get pregnant.
CBS CARES: Will women who take hormones in this cycling manner also experience a return of premenstrual syndrome (PMS) symptoms?
DR. SCHIFF: Yes, they will. I think there is no question that hormone therapy can reproduce premenstrual syndrome. It appears that women who had PMS premenopausally and who are then given hormone therapy may have similar symptoms. That is why some women cannot tolerate having progesterone at all. When they take progesterone, they become irritable and may have fluid retention, difficulty sleeping and all the other symptoms we tend to associate with PMS.
CBS CARES: What are your views on the theory that continuous combined hormone therapy, which simulates a permanent state of pregnancy, could lead to the same medical problems caused by continuous pregnancies (e.g. diabetes, insulin resistance, stroke, blood clots, etc.)?
DR. SCHIFF: There is no evidence that continuous-combined therapy has more risks because it can create a pseudo-pregnancy state.
CBS CARES: What exactly is the significance of the landmark Women's Health Initiative Study?
The background for The Women's Health Initiative is as follows: Estrogens were utilized in the 1960s for alleviation of symptoms. In the 70s, we learned that estrogens used in unopposed fashion could cause endometrial cancer. Thus, by the late 70s, we learned that if we added progesterone you did not have to worry about the development of endometrial cancer. It prevented it.
Then in the 80s, we learned that estrogens prevent osteoporosis. A number of observational studies at that time started to suggest that estrogens might in fact even prevent heart disease. We should keep in mind that the estrogens tended to be given to healthier women who sought out treatment because they were health-conscious, and they were started soon after menopause. All the studies were on estrogens taken in a cyclic fashion, that is, estrogens alone or estrogens in combination with progesterone for about no more than two weeks out of the month.
In the 1990s, there was an effort to have estrogens approved for the prevention of heart disease by the FDA. The FDA initially said yes and then said no, and thus was born the Women's Health Initiative (WHI) of the National Institutes of Health (NIH) to answer the questions. The Women's Health Initiative used two drugs to compare with placebo among its many arms. For Prempro, there were few data even in observational studies that it was effective. The other drug was Premarin, for which there was observational data.
The thrust behind the Women's Health Initiative was not to see if estrogens provide symptomatic relief-that was a given. There were so many observational studies in the early 90s about estrogens preventing Alzheimer's and heart disease, etc., that investigators wanted to design a study to see if they could prove that estrogen prevents all of these chronic diseases. You want to study a population that is at risk for the disease you are trying to prevent. It is important to show that if many people are at risk, that the intervention can make a difference, and you have got to have enough participants for it to be statistically significant. In order to prevent these chronic diseases, they said, we don't want to study symptomatic women, because then the women who got estrogens will know they got estrogens because they will have relief from their symptoms (knowing whether they received estrogens or placebo could bias results). So they deliberately chose asymptomatic women, which automatically bumped the age up. Then you're going to see if you get placebo and there's no prevention, while if you get the active drug there is prevention. If that happens, you can easily show a positive effect while the opposite outcome would be a negative effect.
The study found that there was an increase in stroke and breast cancer with the Prempro (negative effect). The Women's Health Initiative is an important study in that thousands of women were evaluated in a very careful way. The major problem with it is that the hormones used were not used in the traditional way that physicians prescribe them. They studied hormones on a preventative basis in a kind of paradigm where the hormones were not used before.
Thus, there are still questions as to whether if one starts hormones at a younger age, you would see more benefits. At this point, it is not reasonable to take estrogens to prevent heart disease. However, it is certainly reasonable to take hormones for alleviation of symptoms.
With respect to the progesterone component, there was a thought that maybe it was the Provera in Prempro that led to the increased risk for breast cancer, which was not seen in the estrogen-only arm. There are other studies with estrogen only that show an increased risk, but along with progesterone the risk may be even more. I do not know whether it is the continuous combined hormones that cause all the problems. Remember, we have very little observational data on continuous-combined. In addition, the estrogen-only arm had better outcomes. However, in the estrogen-only arm, the women may have had their ovaries removed and this may be an explanation for their decrease in risk. I fully agree that, again, if hormones are started at age 70, and the woman has not seen hormones for ten years, it can be harmful.
CBS CARES: What follow-up studies are being done in light of the WHI study?
DR. SCHIFF: One of the most important ones is the Kronos Study. The lead doctor is S. Mitchell Harman, who used to be at the National Institute of Aging. As I mentioned, the WHI dealt with an older population, one in which we don't traditionally begin treatment. Women in their early 50s who just went through menopause are usually the ones who start taking hormones. So, this is one of the major criticisms of the WHI... that it dealt with an older population. The average woman in the study was actually in her early 60s. So, a follow-up study, not part of the WHI, is looking at younger women who go through menopause and then go on hormone therapy right away to see if it actually prevents heart disease.
CBS CARES: Is it going to explore the breast cancer risk as well?
DR. SCHIFF: Not as a primary motivation, because there may not be enough patients. And in the WHI, they are still doing follow-ups on the patients, and there are other WHI studies just dealing with intervention such as diet, the outcomes of which we have not seen yet.
CBS CARES: What are the short- and long-term benefits and risks of hormone therapy?
DR. SCHIFF: Short-term benefits are alleviation of symptoms and then prevention of osteoporosis. The risks of hormone therapy are stroke, heart disease, phlebitis and breast cancer.
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