Estrogen Deficiency: The Wrong Idea About Menopauseby Dr. Jerilynn C. Prior, Scientific Director, Centre for Menstrual Cycle and Ovulation Research
The largest and best-controlled trial testing whether hormone “replacement” therapy prevented heart disease was stopped three years early in July 2002. The Women’s Heath Initiative (WHI) study included over 16,600 healthy menopausal women without symptoms. These women were randomized to daily conjugated equine estrogen (Premarin, 0.625 mg) plus medroxyprogesterone (Provera, 2.5 mg) or an identical placebo. Hormone therapy increased breast cancer significantly (by 26% over placebo) and caused higher rates of heart attacks (29%), strokes (41%) and blood clots (211%). These risks outweighed this therapy’s significant benefits in preventing osteoporotic fractures of the hip (decreased by 34%) and colon cancer (decreased by 36%).
Menopause (the phase of life beginning one year after the last period) is often viewed as a symptomatic and health-destroying event. Instead menopause is both natural and a welcome relief. Menopause is graduation from 30-40 years of the ovary’s cyclic hormonal demands. I think that the transition into menopause (called “perimenopause”) is the difficult time. I call perimenopause “estrogen’s storm season”!
Since July 2002,hundreds of talk shows and editorials across North America have discussed these results. Many doctors and medical groups have offered criticisms. The usual response is that estrogen and progestin should only be used for bad hot flushes. What is clear is that these Women’s Health Initiative results are hard for established medicine to swallow. However, no one has yet identified what I believe is most important.
What is the most important change since this study?
I believe that the most important change since the Women’s Health Initiative is to view menopause as a normal part of every woman’s life rather than an estrogen deficiency condition. As the late Mary O’Brien, a Canadian nurse-midwife and philosopher, said “it is . . . within the total process of human reproduction that the ideology of male supremacy finds its roots and its rationales."
The results of the Women’s Health Initiative require that society no longer view menopausal women as “estrogen deficient” and therefore needing “estrogen replacement.” Menopause is as normal for women as a period or being pregnant (if we choose). I once joked that calling menopause an estrogen deficiency disease is like saying a headache is an "aspirin-deficiency” condition.
It is important to realize that a fundamental change in the way we see things is difficult for everyone -- for experts, for physicians -- as well as for women.
Why did we believe that estrogen prevented heart disease?
Most scientist believed that estrogen prevented heart disease in menopausal women because many studies showed that thousands of women taking estrogen compared to women not taking estrogen had 30-50 per cent fewer heart attacks. The majority of the studies showed the same good result.
We now know that the women who took estrogen were healthier. This is called a “healthy cohort bias.” Women on estrogen were more likely to be physically active and were less likely to smoke, to be overweight, to have abnormal cholesterol levels, high blood pressure or diabetes. It was these healthy lifestyles, not estrogen treatment, which prevented heart disease.
This is a good news story. It means that living healthy lives prevents the majority of heart attacks in women. There is a 29 per cent increase in heart attacks from estrogen therapy. Healthier women in the observational studies had 30-50% fewer heart attacks. Healthy lives decrease women’s risk for heart attack. This means regular activity (I recommend 30 minutes of walking every day), not smoking, eating right to prevent abnormal cholesterol and blood sugar levels and high blood pressure. Effective treatments are available if, because of inherited risks, a good lifestyle is not sufficient.
Could we have known that estrogen caused heart attacks before this study?
Yes. Two randomized, controlled studies in men who had heart attacks tested the idea that estrogen there would prevent further heart disease. These were also stopped early because the men on estrogen experienced more heart attacks and blood clots. A randomized controlled trial of estrogen plus progestin therapy in women who already had heart disease also showed no improvement on hormone therapy. "As a scientist, I had, long before the recent results, questioned the notion that estrogen prevents heart disease."
Should doctors stop prescribing or women stop taking ovarian hormone therapy (OHT)?
That doesn’t make sense! Although we now know that healthy menopausal women without or with bearable night sweats don’t need treatment, some menopausal women would benefit from OHT. Estrogen and progesterone are the most effective therapies we have for night sweats or hot flushes that are disturbing.
A woman who has survived breast cancer, even if she has hot flushes and night sweats, should not take estrogen. However, I believe that progesterone is safe for her. Even progesterone should only be used if she is disturbed by her symptoms. Two randomized double blind trials of balanced hormone doses of progesterone, estrogen, estrogen with progesterone and a placebo were applied as a crème to one of each woman’s breasts. After 11 days of treatment, a small amount of tissue was removed from the treated breast and analyzed for the cell growth rate as a marker of the risk for cancer. Estrogen increased but progesterone decreased breast cell growth. Estrogen with progesterone also showed decreased growth. These results suggest that progesterone would decrease the risk for breast cancer.
Are there any good reasons to take ovarian hormone therapy?
There are three good, scientific and justifiable reasons for ovarian hormone therapy (OHT). Night sweats that that are chronic and disturbing are the first good reason for OHT. These may sufficiently disturb women’s well-being and metabolism that, like chronic pain, they require treatment. Night sweats may also be detrimental for bone and increase the risk for osteoporosis.
A woman with early menopause (before age 40 or 45 whether because of surgery, radiation or for other reasons) has missed out on part of the normal 30 to 40 years of cyclic high estrogen and progesterone levels. She needs balanced ovarian hormone therapy until she reaches age 51, the average age for menopause. Then she can begin tapering estrogen treatment.
Osteoporosis, broken bones with little force (like a fall from a standing height or less) and the bone loss that normally occurs during the years after menopause can be prevented by estrogen with progesterone therapy. And we now know OHT prevents hip as well as the more common back (vertebral) and wrist and ankle fractures. Osteoporosis at the time of menopause, especially if she also has severe hot flushes/night sweats is the third and final good reason for OHT.
Have you changed how you prescribe ovarian hormone therapy since WHI?
Yes. I will never again prescribe estrogen as a pill. When a pill of estrogen is swallowed it travels through the stomach to the liver and stimulates it to make new proteins. Some of these increase the risks for blood clots, others increase the risks for high blood pressure or migraine headaches. Evidence suggests (although we don’t have randomized controlled trial results) that estrogen absorbed through the skin (called “transdermal” as patch, crème or gel) will carry less risk. Progesterone and medroxyprogesterone have been tested over and over and never been shown to increase blood clots.
I continue to recommend that no one take estrogen for more than four or five years. This has been my practice for at least ten years. However, as discussed above, women with early menopause can safely take estrogen therapy until they reach age 51. In contrast to the time limit on estrogen, I believe that progesterone or medroxyprogesterone are safe for as long as they are needed.
I’ve decided to stop estrogen therapy. How should I do it?
If you have ever had hot flushes, I would recommend stop estrogen very gradually over three or four months and while taking full dose, daily progesterone. If you have osteoporosis or low bone density, you need to start etidronate or another bisphosphonate anti-bone resorption medicine before tapering estrogen (see Stopping Estrogen Therapy).
When you have been off the estrogen for several months, if you have no reason for progesterone (such as night sweats or low bone density) you could also stop progesterone.
Do you agree with giving estrogen without progesterone following a hysterectomy?
No. That idea doesn’t make sense—progesterone and estrogen work together in the normal menstrual cycle and in every tissue. In menopause, progesterone should always be used whenever estrogen is taken. Even if she is without her uterus, a menopausal woman continues to have breasts, bones and a brain that need progesterone.
Progesterone therapy should be taken daily and in a full dose to oppose the tendency of estrogen to cause cells to grow (proliferate and increase cancer risk). In bones estrogen slows bone loss, however, progesterone acts to stimulate bone growth (formation). Estrogen plus low dose progestin causes a greater increase in spinal bone density than estrogen alone.
How would you sum up your thoughts about Ovarian Hormone Therapy?
The first big controlled trial of OHT was stopped early because pill estrogen and low dose medroxyprogesterone therapy were not safe in healthy menopausal women. This proves that menopause is a normal part of life, not estrogen deficiency and doesn’t need hormone treatment. However, there remain three good reasons for menopausal ovarian hormone therapy—early menopause, osteoporosis with night sweats, and disturbing hot flushes/night sweats. If you have been taking estrogen for the wrong reasons or for longer than five years and want to stop, with the help of full dose daily progesterone and the estrogen patch you can stop it gradually over about four months.
Get more information from these articles:
Writing Group for the Women's Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative Randomized Control trial. JAMA 2002; 288: 321-333.
Prior JC: Perimenopause: the complex endocrinology of the menopausal transition Endocr.Rev. 1998; 19: 397-428.
O'Brien M: The politics of reproduction. London: Routledge and Kegan Paul, 1981; 1-240.
Prior JC: One voice on menopause. J.Am.Med.Women Assoc. 1994; 49: 27-29.
Prior JC: Critique of estrogen treatment for heart attack prevention. A Friend Indeed 1992; VII: 3-4.
Coronary Drug Project Research Group: Initial findings leading to modifications of its research protocol. J Am Med Assoc 1970; 214: 1303-1313.
Coronary Drug Project Research Group: Findings leading to the discontinuation of the 2.5 mg/day estrogen group. J Am Med Assoc 1973; 226: 652-657.
Hulley S, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J Am Med Assoc 1998; 280: 605-613.
Prior JC: Postmenopausal estrogen therapy and cardiovascular disease (letter) N Engl J Med 1992; 326:705-6
Foidart J, et al: Estradiol and progesterone regulate proliferation of human breast epithelial cells. Fertil.Steril. 1998; 5: 963-9.
Chang-King J et. al. Influence of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil.Steril. 1995; 63: 785-791.
Lindsay R et. al. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. J Am Med Assoc 2002; 287: 2668-2676.
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