Major medical groups have recommended that hormone therapy not be used as first-line treatment for women with abnormal cholesterol levels.

Women who choose to take hormones after menopause tend to be more affluent, more health conscious and have more access to health care.

or women who reach menopause, deciding about hormone replacement therapy is a bit like trying to solve a Rubik’s cube. Every time you get one part of the puzzle in place, it seems to rearrange another area you thought was set. The complete picture both doctors and patients want to see is elusive and constantly changing.

Hormone replacement therapy affects multiple aspects of a woman’s health. It counters the immediate effects of estrogen depletion such as hot flashes, vaginal dryness and urinary tract infections that bother many women. Numerous studies also show that it prevents or slows the sudden loss of bone that occurs in the years immediately following menopause, setting the stage for osteoporosis in later life. And until recently physicians have confidently prescribed hormone therapy as a means of preventing or treating heart disease, the single biggest killer of women in the postmenopausal years.

But a number of recent studies have cast doubt on estrogen’s role in the prevention of heart disease. The widespread belief in estrogen’s favorable effects on the heart was based on observational studies and on clinical studies of the positive effects of estrogen on blood cholesterol levels.

The Nurses’ Health Study has provided valuable observational data on a large group of women over many years. It has consistently showed that women who use hormone therapy have a lower risk of heart disease and heart-related deaths than women not taking hormone therapy. A number of other observational studies have supported these findings. Overall, observational studies of the benefits of hormone replacement therapy showed a 35 to 50 percent reduction in the risk of coronary heart disease.

Observational studies have a number of drawbacks, however. The subjects in the Nurses’ Health Study are better educated and better informed regarding health care issues than women in the general population. A lower rate of heart disease may be attributable to a healthier lifestyle and diet rather than to hormone therapy.

Other observational studies of women taking hormone therapy have shown a similar bias. Women who choose to take hormones after menopause tend to be more affluent, more health conscious and have more access to health care than women not taking hormones. Any of these factors could be responsible for a lower rate of heart disease.

Evidence from Controlled Trials
A number of controlled, clinical trials have questioned estrogen’s benefits to the heart.

The results of the Heart and Estrogen/progestin Replacement Study (HERS) were published in 1998. HERS, studying 2763 women with established heart disease for a mean of 4.1 years, was the first large-scale randomized trial comparing women taking hormone therapy with women taking a placebo. A powerful, well-designed study, HERS found that women taking hormone therapy and those on placebo had a similar rate of heart attack and deaths from heart disease over the four years. Even more unexpected, however, was that the group taking hormones had a much higher rate of heart attack and death in the first year of the study, and a lower rate from the third year onward.

This same pattern of early risk and later apparent benefit was seen in the Hormone Replacement Therapy trial of the Women’s Health Initiative (WHI) , a long-term study of the effects of hormone therapy and the first large-scale trial of women without heart disease. The WHI trial is not scheduled to end until 2005, but preliminary results were released in April, 2000.

At that point, some three years into the study, the trial director informed the women participating in the study of a small but significant trend toward early heart disease, affecting some one percent of the group taking hormone therapy.

Women were advised that because the elevated risk was observed in the first two years of hormone therapy it was safe for them to continue since they had passed the high-risk period.

A third study, the Estrogen Replacement and Atherosclerosis (ERA) trial, measured changes in the arteries of women with established heart disease. Researchers used angiography to measure the progression of heart disease in 309 women. Although hormone therapy lowered cholesterol levels, it did not alter the progression of coronary atherosclerosis in the women receiving hormone therapy.

As a result of accumulating evidence from randomized trials questioning the ability of hormone therapy to alter the course of heart disease, the American Heart Association and the American College of Cardiology issued a joint position statement recommending that hormone therapy not be used as a first-line treatment for women with abnormal lipid levels. Instead, the two medical groups recommend that these women be treated with the statin drugs that have been shown in randomized trials to benefit both women and men with known heart disease. The statin drugs lower blood cholesterol levels and are also associated with a significantly lower risk of death from heart disease in those taking the drugs.

Results from CARE (Cholesterol and Recurrent Events Trial), a study of women with mildly elevated cholesterol (average total cholesterol was 209), showed that those who took 40 milligrams of pravastatin daily were 46 percent less likely to suffer a second major heart attack than women who took a placebo.

Several studies show that, although prescribed for the heart, statins may have a positive effect on bone mass. A large analysis of statin studies found that women currently using statins may have a 45 percent lower risk of fractures compared with nonusers. Further studies are needed to confirm this, however.

A woman considering hormone replacement therapy needs to be fully informed of the overall risks and benefits of the therapy and of reasonable expectations of individual risks and benefits. She should find a physician willing to take the time to discuss the issue and answer questions in terms she can understand. She can also request additional information from her physician.

When the WHI study is completed in 2005, women and their physicians will have better data to work with. Each new study locks one more piece of the puzzle in place, gradually bringing together a clearer view of a highly detailed and complex picture.

REFERENCES:
F. Al-Azzawi, “ The Menopause and Its Treatment in Perspective,” Postgraduate Medical Journal, May 2001.
John Blakely, “The Heart and Estrogen/Progestin Replacement Study Revisited,” Archives of Internal Medicine, October 23, 2000.
“Heart Lines–Hormone Replacement Therapy and Stroke Risk,” Harvard Health Letter, July 2001.
David Herrington, “Effects of Estrogen Replacement on the Progression of Coronary-Artery Atherosclerosis,” JAMA, October 11, 2000.
“Hormone Replacement Therapy–Another Chapter in the Heart and Estrogen Story,” Harvard Women’s Health Watch, April 2000.
Deborah Kaplan, “HRT and CHD: Balancing Risk and Suggested Benefit,” Patient Care, October 23, 2000.
Lori Mosca, “The Role of Hormone Replacement Therapy in the Prevention of Postmenopausal Heart Disease,” Archives of Internal Medicine, August 14, 2000.
“Risk/Benefit Considerations for Hormonal Therapy: Ocs and HRT,” Family Practice News, January 15, 2001.
Carol S. Saunders, “ERT Does Not Slow Preexisting Heart Disease,” Patient Care, October 30, 2000.
Kathryn Senior, “The Double-Edged Sword of Postmenopausal Hormone Therapy,” The Lancet, January 6, 2001.
“This Round: Risks of Hormone Therapy May Outweigh Benefits,” Consultant, March 2001.
“Will Statins Unseat Estrogen?” Harvard Health Letter, November 2000.

Major Killer of Women
Cardiovascular disease is the leading killer of women in the United States, responsible for approximately half a million deaths annually. Uncommon before menopause, heart disease is seen primarily in postmenopausal women.
Modifiable risk factors for heart disease include smoking, being overweight, inactivity, high blood pressure, high cholesterol levels, and adult onset diabetes.
[SOURCE: Lori Mosca, “The Role of Hormone Replacement Therapy in the Prevention of Postmenopausal Heart Disease,” Archives of Internal Medicine, August 14, 2000]

• breast tenderness, which usually improves after 3 or 4 months;
• headaches;
• nausea and upset stomach, which can occur in women taking oral estrogen.

Side effects of progestin include:

• irregular bleeding;
• PMS type symptoms including fluid retention, weight gain and breast tenderness;
• acne and skin eruptions.

Women who experience unacceptable side effects of HRT should report symptoms to their doctors. Side effects may be short-lived or can often be overcome by changing the dose, the schedule or the type of hormone preparation.
[SOURCE: F. Al-Azzawi, “The Menopause and its Treatment in Perspective,” Postgraduate Medical Journal, May 2001]

Thin Women Gain More
An observational study of postmenopausal women found that current estrogen users had the largest decrease in risk of coronary heart disease. Not all women taking HRT benefitted equally, however.

Hysterectomy and Hormone Therapy
By age 60, one third of American women have had a hysterectomy. Women who have a hysterectomy before natural menopause experience an abrupt loss of estrogen and are typically prescribed etrogen replacement.

Women who have a hysterectomy after menopause may choose to take estrogen to counter postmenopausal changes.

Women who have not undergone a hysterectomy take estrogen plus a progestin to protect against endometrial cancer. Women who have had a index (less than 22) showed the greatest benefit. Obese women (those with a body mass index greater than 30), showed no reduced risk of coronary heart disease with HRT.

Experts say this effect may be explained by the fact that estrogen is found in adipose tissue. Obese women don’t experience the same low estrogen levels as thinner women.
[SOURCE: “Hormone Replacement’s Cardioprotective Effect Not Seen in Obese Women,” Geriatrics, April 2001]

HRT Has Multiple Benefits
Women who use hormone replacement therapy after menopause experience a number of positive physical benefits.

Hormone therapy manages hot flashes, prevents bone loss and lowers the risk of dryness, atrophy and other adverse symptoms in both the genital and urinary tracts. There is also data suggesting that HRT use lowers the risk of Alzheimer’s disease and of colorectal cancer, protects against tooth loss and benefits overall mortality before age 80.
[SOURCE: “Risk/Benefit Considerations for Hormonal Therapy,” Family Practice News, January 15, 2001]

Side Effects Discourage Use
Approximately 30 percent of postmenopausal women begin hormone replacement therapy (HRT), but no more than 50 to 60 percent continue with the therapy past one year. Many women stop taking HRT because of concern about the reported increase in the risk of breast cancer with long-term use. Other women stop because of unwanted side effects.

Make an Informed Decision
One of the frustrations about making a decision regarding hormone replacement therapy is the scarcity of data based on long-term clinical trials involving large numbers of women. Two such trials are currently in progress but with final results some years off.

The United Kingdom Women’s International Study of Long-Duration Oestrogen after Menopause (WISDOM) will study the effect of hormone therapy on predominantly healthy postmenopausal women.

In the United States, the Women’s Health Initiative is studying 27,000 healthy postmenopausal women randomly assigned to take estrogen plus progestin, estrogen (for women who have had a hysterectomy) or a placebo. This study will end in 2005.
After that date women will have a valuable source of data on which to base decisions about HRT.
[SOURCE: Deborah Kaplan, “HRT and CHD: Balancing Risk and Suggested Benefit,” Patient Care, October 30, 2000]