Combination Hormone Therapy (CHT) Poses Heart Disease Risk for Postmenopausal Women

New analyses from the Women’s Health Initiative (WHI) confirm that combination hormone therapy increases the risk of heart disease in healthy postmenopausal women. Researchers report a trend toward an increased risk of heart disease during the first two years of hormone therapy among women who began therapy within 10 years of menopause, and a more marked elevation of risk among women who began hormone therapy more than 10 years after menopause. Analyses indicate that overall a woman’s risk of heart disease more than doubles within the first two years of taking combination HT.

The difference in the initial level of risk does not appear related to age, based on findings that the increased risk of heart disease was similar between women in their 50s on combination hormone therapy and women in their 60s.

“Today, most women who take hormone therapy for menopausal symptoms begin therapy shortly after menopause. Based on today’s report, even these women appear to be at increased risk of heart disease for several years after starting combination hormone therapy,” noted Susan B. Shurin, M.D., NHLBI acting director. “It is clearer than ever that women who are considering postmenopausal hormone therapy for menopausal symptoms should discuss their risk of heart disease and other risks – such as breast cancer, stroke, and dangerous blood clots – with their doctors before starting therapy.”

Jacques E. Rossouw, M.D., chief of the NHLBI Women’s Health Initiative Branch and a coauthor of the paper, added, “Although the number of recently menopausal women who would be expected to suffer a heart attack during the first years of combination hormone therapy is small, the risk is likely to be real. Our findings continue to support FDA recommendations that postmenopausal hormone therapy should not be used for the prevention of heart disease.”

Combination hormone therapy includes progestin in combination with estrogen. Adding progestin is known to prevent endometrial cancer in women with a uterus. Today’s findings do not apply to women who have had a hysterectomy and take estrogen-only hormone therapy. Similar analyses on the results of the clinical trial of estrogen only therapy are planned.

Researchers from the Harvard School of Public Health and the NHLBI reanalyzed data from the landmark WHI clinical trial of the effects of combination hormone therapy in 16,608 postmenopausal women with an intact uterus, ages 50 to 79 years (average age of 63) at enrollment.

In the new analyses, the researchers compared the effects of hormone therapy on heart disease risk among women who began hormone therapy within 10 years of menopause and women who began therapy more than 10 years after menopause. The researchers used models that adjusted for adherence, or the actual amount of medication that participants took during the study. They also studied the effects of hormone therapy on heart disease over time (up to eight years). In addition, they compared the findings with similar analyses of 34,575 women in the Nurses Health Study, an observational study with an average follow-up of 9.3 years. The researchers report similar effects of hormone therapy from both studies.

In the WHI clinical trial of estrogen-plus-progestin, 8,506 participants were randomly assigned to receive a combination of estrogen (0.625 milligrams of conjugated equine estrogens per day) plus progestin (2.5 mg of medroxyprogesterone acetate), and 8,102 women were given placebo (inactive pill). The study was stopped in 2002 after an average of 5.6 years of treatment due to an increase in breast cancer in the women on hormone therapy. Compared to women on placebo, women on combination hormone therapy were also at increased risk of stroke, dangerous blood clots, and heart disease, while their risk of colorectal cancer and hip fractures was lower.

Overall, among the 8,506 women assigned to combination hormone therapy during the study, there were 188 cases of coronary heart disease (80 in the first two years), compared to 147 heart disease cases (51 in the first two years) among the 8,102 women on placebo. When adjusted for adherence, the analysis shows that women on combination hormone therapy were about 2.4 times more likely to develop heart disease in the first two years. At eight years, the women on combination hormone therapy were 69 percent more likely to develop heart disease.

The new analyses also showed:

Women who were within 10 years of menopause had a trend toward an increased risk of heart disease, with a 29 percent higher risk at two years from the start of hormone therapy. Although the increased risk of heart disease was not statistically significant, this finding is consistent with a similar analysis of data from the larger Nurses Health Study.

Women who started combination hormone therapy less than 10 years after menopause remained at increased risk of heart disease on average for about six years, after which those in the treatment group appeared to have a lower risk of heart disease compared to similar women who were not on combination hormone therapy. In the nurses study, the initially increased risk on combination hormone therapy changed toward lower risk of heart disease after about three years.

In contrast, women who started hormone therapy 10 years or more after menopause were nearly 3 times more likely to develop heart disease within the first two years of treatment compared to women on placebo. These women continued to be at increased risk of heart disease throughout the 8 years of follow-up.

It is not clear why the heart disease risk appears to be higher in women who start combination hormone therapy a decade after menopause than in women who begin combination hormone therapy within 10 years after menopause. According to Sengwee Toh, Sc.D., lead author of the paper and now an instructor in the Department of Population Medicine, Harvard Medical School, “This study suggests that the risk of heart disease may depend on when women start their combination hormone therapy and how long they are on this treatment. Future investigations should consider both of these aspects.”

The WHI is a major 15-year research program designed to address the most frequent causes of death, disability, and poor quality of life in postmenopausal women: cardiovascular disease, cancer, and osteoporosis. The principal findings from the two WHI hormone therapy trials, which studied 27,347 postmenopausal women on estrogen plus progestin, estrogen-alone, or placebo, found that the overall risks of long-term use of hormone therapy outweigh the benefits. Both of these trials were stopped early because of increased health risks and failure to prevent heart disease, a key question of the studies.

The NHLBI collaborates on the WHI with the National Cancer Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, and the Office of Research on Women’s Health, all parts of the NIH. Wyeth-Ayerst Research provided the medication and placebo for the hormone study.

Source: em>Annals of Internal Medicine (2/16/2010); National Institutes of Health (2/15/2010)

Concerns Voiced Over Long-Term Effects of Synthetic Progestins

In a study done at the University of Oregon, the widely used synthetic progestin medroxyprogesterone acetate (MPA) decreased endothelial function in premenopausal women. The finding, researchers said, raises concerns about the long-term effects of MPA and possibly other synthetic hormones on vascular health in young women.

The vascular endothelium lines the inside of blood vessels. In recent years, it has been found to be a dynamic organ that serves an important role in the prevention of atherosclerosis. "The logical conclusion of this study is that over a long period of time it would not be good to have exposure to an agent that is reducing blood vessel flexibility, because it could be associated with the development of heart disease or related problems," said co-author Dr. Paul F. Kaplan, a long-time Eugene gynecologist and senior researcher in the UO’s human physiology department. He stressed, however, that a longer, larger study is needed.

MPA is the active ingredient of Provera, used to treat abnormal uterine bleeding, induce menstrual cycles and relieve symptoms of menopause. Depo/Provera, an injectible long-lasting contraceptive in common use by many young women, contains MPA as an active ingredient. MPA was also used in the Women’s Health Initiative (WHI) including a clinical study on hormone replacement. This was stopped because of health concerns in post menopausal women. Millions of women use hormone therapies with a variety of progestin types for contraception.

The UO study is among the first to target the impact of MPA in premenopausal women. Fourteen women, 19-27 years old, participated in the study after exams to screen out various health conditions. The five-member UO team—led by Jessica R. Meendering, a former UO doctoral student now a professor of exercise science at the University of Nebraska in Omaha—studied the effects of the sex hormone estradiol by itself and in combination with MPA on endothelial function of the brachial artery. The health of the endothelium in this artery has been shown to be a telling proxy for the coronary arteries and a good predictor of cardiovascular risk.

When researchers gave an oral version of MPA to determine its impact, they found that it wiped out the positive effects on endothelial function that estradiol had provided. MPA reduced the function by reducing the brachial artery’s ability to dilate—grow bigger in diameter—in response to the stress of changing blood flow, Kaplan said.

Source: Journal of Physiology: Heart and Circulatory Physiology

Smoking May Lead to Early Menopause

Regular smoking has been known to cause more than 85 percent of all deaths due to lung cancer. It may also lead to many other types of cancer and a large array of other health-related issues.

According to BMC Public Health, early menopause onset, before the age of 45, is more than twice as likely in women who smoke heavily.

The study also looked at effects of passive smoking, alcohol, and coffee consumption and found that these activities do not have a significant effect on early menopause.

Treatment Options for Menopause-related Hot Flashes

There are numerous treatment options for menopause-related hot flashes, from pharmaceutical drugs, to alternative therapies and exercise.
Hormones might not be safe for everyone, and some supplements may not be safe or effective.

Since supplements are not widely tested or regulated by the FDA, it is more difficult to determine their effectiveness.

Alternative therapies, such as black cohosh or Chinese herbs are widely used, and some have been shown to have a positive placebo effect. However, researchers have shown that using black cohosh, for example, is not effective.

Other pharmaceutical drugs, such as Selective serotonin reuptake inhibitors (SSRI’s) have been found to significantly reduce hot flashes in women with menopause, though these anti-depression drugs have not been approved by the FDA for treatment of menopause symptoms

(Drugs such as fluoxetine (Prozac), paroxitene (Paxil) and venlafaxine (Effexor) have all been found to help relieve menopause symptoms.

Several studies have shown that women who exercise regularly have fewer hot flashes, likely due to increased endorphin production.

Source: ABC News/KGO (1/3/07) 

“Induced Menopause” Can Protect Women’s Fertility After Chemotherapy

A therapy that temporarily shuts down the ovaries could protect the fertility of women with cancer who are undergoing chemotherapy, say researchers.

Australian scientists used a drug to turn off a hormonal "switch" in the brain that triggers ovulation.
Once the woman’s chemotherapy has ended, the drug is stopped and the ovaries switch back on with their store of eggs in tact.

Source: BBC News (7/4/07) 

How the NIH Mis-Read 2002 Menopause Hormone Study

On July 9, 2002, federal government health officials announced that they had halted a major study of menopause hormones, saying the drugs increased a woman’s risk of heart attack by 29%.

But in the five years since, it’s become clear that some aspects of what was initially reported from the $725 million Women’s Health Initiative study were either misleading or just wrong.