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Beyond “Estrogen Deficiency”—news from Women’s Health Initiative

The USA’s National Institutes of Health just announced that the Estrogen arm of the Women’s Health Initiative was stopped early (1). Estrogen treatment in women who had undergone hysterectomy was associated with neither benefit nor harm for heart disease and caused a 40% increase in stroke (1).

No one can ever again say that estrogen therapy prevents heart disease. This breaking news is good news for menopausal women. Based on non-randomized studies most experts believed that estrogen treatment decreased heart attacks by 50% in menopausal women. However, because observational studies cannot document cause, the National Institutes of Health organized a large two-armed randomized controlled trial to test the idea. One arm of the Women’s Health Initiative (WHI) trial was in women who had not had hysterectomy—participants were randomized to Estrogen plus Progestin or placebo. The other arm was in women with hysterectomy who were randomized to Estrogen or placebo. The combined hormone therapy arm was stopped in July 2002 because it caused more harm than benefit. Now, March 2 2004 the USA’s National Institutes of Health announced that it had stopped the estrogen arm of the WHI early—after seven rather than a planned eight and a half years (1). The reason—strokes were increased more on estrogen than on placebo pill and estrogen clearly didn’t prevent heart disease.

So far we only have a press release about the WHI Estrogen arm results. No scientific study has yet been published. When we have more information this article will be updated.

In July 2002 the Estrogen plus Progestin arm of the WHI study was stopped early (2). That study showed combined hormone therapy caused more heart attacks, strokes, diseases related to blood clots and breast cancer than placebo and that these risks were greater than the prevention of hip fracture and colon cancer benefits hormone therapy also caused (2).

Based on these new and important scientific results, if you decide to go off hormone therapy stop estrogen gradually (see “Stopping Estrogen Therapy”). If you have troubling hot flushes/night sweats look at “Natural Therapies for Hot Flushes”. If you try all the non-prescription methods and still are troubled by night sweats disturbing sleep, two alternatives to estrogen have been shown to be effective in randomized controlled trials. The first one is natural progesterone as a cream (20-mg twice a day) (5). The second non-estrogen treatment shown to be effective for hot flushes is 20 mg a day of medroxyprogesterone (6). Clinical data also suggest that oral micronized progesterone (Prometrium®) in a dose of 300 mg at bedtime is effective—we are currently performing a randomized, double blind placebo-controlled trial to test that idea.

The Age of Estrogen “Replacement” is now over. Menopausal women have been guinea pigs in a massive, decades long unscientific “experiment” (7). For no benefit, one woman of every 230 ages 50-59 who takes estrogen for five years will suffer harm compared with women on placebo (8). One woman of every 150 ages 60-69 taking estrogen for five years will experience something harmful that didn’t occur on placebo, like a stroke, a blood clot or a breast cancer (8).

The idea of replacement is a good one for diseases like underactive thyroid and childhood onset insulin-requiring diabetes that involve true lack of hormone. But deficiency is not an accurate way to understand menopause. In contrast to those diseases, menopause is a normal phase of every woman’s life. It is a time of normally low estrogen levels.

Beware of authorities saying that the very low dose medroxyprogesterone, not estrogen, was responsible for the differences between results of the Estrogen and the Estrogen plus Progestin arms of the WHI. Many experts continue to believe that estrogen treatment will “fix” all menopausal women—it’s easier to blame progestin than to face the harmful effects of estrogen therapy shown by the WHI. It is already clear that strokes are caused by estrogenstroke increased in both arms of WHI and estrogen is the only hormone shared by both. Secondly, it is important to realize that whether or not a study shows differences from placebo depends on what we call its “power.” That means that before a study starts scientists try to figure out how many participants they need to be 80% sure to show a significant effect. The Estrogen arm only had power to show heart attack prevention and not increased breast cancer (3). The Estrogen arm of WHI had less than 11,000 women while the Estrogen plus Progestin arm enrolled almost 17,000. The other difference (that many breast cancer experts don’t know) is that women who have had hysterectomy surgery have a significantly lower risk than normal for breast cancer (4). Therefore to show that estrogen caused breast cancer would have required more women than were enrolled and many more than were in the Estrogen plus Progestin arm.

These important data should once and for all cause death of the “estrogen replacement” idea. Now at last we can act on what we already know about preventing heart attacks in women. It cannot be found in a pill. Heart attack prevention for menopausal women includes regular exercise, healthy diets (lots of vegetables and fruit), keeping weights normal, avoiding or stopping smoking and, if needed, treating abnormal lipid levels and diabetes. Also, and even more important, maybe we can now start to learn about the normal changes with aging in menopausal women.

Reference List

  1. Women’s Health Initiative Website. NHLBI Advisory for physicians on the WHI trial of conjugated equine estrogen versus placebo. Women’s Health Initiative Website . 2004.
  2. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in health postmenopausal women: principal results from the Women’s Health Initiative Randomized Control trial. JAMA 2002; 288:321-333.
  3. The Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 1998; 19(1):61-109.
  4. Kreiger N, Sloan M, Cotterchio M, Kirsh V. The risk of breast cancer following reproductive surgery. Eur J Cancer 1999; 35:97-101.
  5. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstetrics and Gynecology 1999; 94:225-228.
  6. Schiff I, Tulchinsky D, Cramer D, Ryan KJ. Oral medroxyprogesterone in the treatment of postmenopausal symptoms. Journal of the American Medical Association 1980; 244:1443-1445.
  7. Seaman. The greatest experiment ever performed on women: exploding the estrogen myth. New York: Hyperion, 2003.
  8. Beral V, Banks E, Reeves G. Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet 2002; 360(9337):942-944.
Life Phase: 
Updated Date: 
April 8, 2014

Estrogen’s Storm Season: Stories of Perimenopause

Estrogen's Storm Season

by Dr. Jerilynn C Prior

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