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)

Hormone Replacement Therapy (HRT) and Its Effects on Skin Appearance

For many women, hormone replacement therapy (HRT) can alleviate the physical symptoms associated with the change of life. But despite the initial hype generated by post-menopausal women who noticed a marked improvement in their skin’s appearance while on HRT, dermatologists argue that scientific studies of estrogen do not show definitive improvements for skin rejuvenation of photodamaged skin and the potential risks when used long-term outweigh any potential skin benefits.

At the American Academy of Dermatology’s Summer Academy Meeting 2009 in Boston, dermatologist Margaret E. Parsons, MD, FAAD, assistant clinical professor of dermatology at the University of California at Davis in Sacramento, reviewed studies that demonstrate mixed results when examining whether or not estrogen improves the appearance of the skin and why patients should opt for tried-and-true cosmetic therapies instead.

“Based on the research conducted thus far, it does not appear that topical or oral estrogens are a viable long-term solution for improving sun-damaged or aging skin,” said Dr. Parsons. “In my practice, I do not prescribe estrogens for skin rejuvenation because of the lack of consistent data to support their use and the known risks of prolonged estrogen therapy – including an increased risk of breast cancer.”

Estrogens are a group of hormones that play a key role in regulating many aspects of a woman’s overall health, including reproduction. Certain parts of the body contain cells that are more receptive to the effects of estrogen than others, including the face. Dr. Parsons noted that estrogens benefit the skin in many ways, including an increase in collagen content, water retention and elasticity.

During pregnancy when estrogen levels are at their highest, women experience thicker hair and glowing skin. On the other hand, post-menopausal women may
notice that their skin does not have the same elasticity as it once did and that it is drier than normal.

In order to treat the most common symptoms associated with menopause – including hot flashes, mood swings and vaginal changes – physicians often prescribe hormone replacement therapy (HRT) to boost the body’s estrogen levels that drop dramatically during this change of life. However, when the results of the Women’s Health Initiative (WHI) study were announced in 2002, the way HRT was viewed to treat post-menopausal women changed significantly. For example, the WHI study found that women on long-term HRT could be at an increased risk for breast cancer and that the overall health risks of this therapy could outweigh the possible benefits. From that point on, HRT was prescribed more conservatively with lower dosing options and individualization based on each woman’s own health history.

Since there were reports of some women on HRT noticing an improvement in their skin, studies were conducted to determine if these results could be validated. Dr. Parsons explained that results of multiple studies examining the relationship between estrogens and skin improvement were inconclusive.

For example, one study examined whether low-dose hormone therapy improved aging skin in 485 women who were on average five years post-menopausal. Published in the September 2008 issue of the Journal of the American Academy of Dermatology, the study concluded that estrogen supplementation did not provide any significant improvement in sun-damaged skin.

“Although this study found no obvious skin benefits in this particular group of women, another study that looked at women who began HRT at the onset of menopause – and did not wait to start treatment like the other group – did experience noticeable improvements in their skin,” said Dr. Parsons. “These
studies pose unanswered questions as to the timing and duration of prescribing HRT to produce skin benefits. For this reason, the jury is still out as to whether estrogens can be effective for aging skin.”

In addition, another study showed that applying topical estrogen to sun-damaged facial skin and sun-protected skin on the hip of post-menopausal women resulted in stimulated collagen production and less wrinkling in the sun-
protected hip skin, but no noticeable improvement in the sun-damaged facial skin.

Dr. Parsons added that more research will likely continue in the future to examine the possible benefits of estrogen for improving aging skin. Until then, she stressed that there are many effective therapies that dermatologists regularly use to address the common signs of aging – including retinoids, alpha-hydroxy acids and other topical therapies, as well as chemical peels, lasers, botulinum toxin and skin fillers, to name a few.

“The best advice I can offer my patients to improve their overall skin health is to wear sunscreen with a sun protection factor (SPF) of at least 30, don’t smoke and use a topical retinoid,” said Dr. Parsons. “When it comes to minimizing the cumulative effects of sun damage, an ounce of prevention really does go a long way.”

Increased Risk of Breast Cancer Recurrence Tied To High Levels of Estrogen

Women whose breast cancer returned after treatment had almost twice as much estrogen in their blood than did women who remained cancer-free, according to a newly published study.

The study’s lead author, Cheryl L. Rock, Ph.D., a professor in the Department of Family and Preventive Medicine at the University of California, San Diego, said that high levels of estrogen—which lead to the initial development of breast cancer—could be associated with an increased risk of recurring cancer.

"While this makes sense, there have been only a few small studies that have looked at the link between sex hormones in the blood and cancer recurrence," she said. "This is the largest study to date and the only one to have included women taking agents such as tamoxifen to reduce estrogen’s effect on cancer growth."

"What the results mean for women who have already been treated for breast cancer is that they should do as much as they can to reduce estrogen in their blood, such as exercising frequently and keeping weight down," she added. "Taking anti-estrogen drugs like tamoxifen may not completely wipe out the hormone’s effect in women who have high levels of estrogen."

The Women’s Healthy Eating and Living Study (WHEL) provided participants for the breast cancer study, a dietary intervention trial that monitored 3,088 women treated for breast cancer but cancer-free when recruited for the study. Subjects were placed in two groups—one that ate a " normal" healthy diet, one that ate extremely large amounts of fruits, fiber and vegetables. After 7 years, participants were checked for breast cancer, which was about the same for each group. Researchers interpreted the findings to mean that a normal diet that incorporates the U.S. Food and Drug Administration guidelines for recommended amounts of fruits and vegetables is sufficient.

In the current study, 153 WHEL participants whose cancer had recurred were matched with 153 participants who remained cancer-free. These pairs were alike in terms of tumor type, body size, age, ethnicity, use of chemotherapy and other variables. Two-thirds of the participants were using tamoxifen, Rock said.

When they enrolled, researchers tested the women’s blood for concentrations of the steroid hormones estradiol (the primary human estrogen) and testosterone. They analyzed different forms of estradiol and testosterone in the blood, such as how much was bound to transport proteins (such as to the sex hormone binding globulin, or SHBG) and how much was "free" circulating and able to enter a cell.

The study was published in the March issue of Cancer Epidemiology, Biomarkers and Prevention, a journal of the American Association for Cancer Research.

Decrease in Hormone Therapies Linked to Decline in Breast Cancer

Researchers claim that an analysis of patients’ treatment records at a large HMO indicate that reduced use of hormone replacement therapy (HRT) may be the cause behind declining breast cancer rates.
They pointed out that, as some studies suggest, this decline is not due to reduced use of mammography.

The research indicates that one of the main causes of the decline is due to the reduction in post menopausal hormone therapy in 2003, in response to results of Women’s Health Initiative that linked breast cancer to hormone replacement therapy.

Growth of small tumors slows down when hormone replacement therapy is discontinued delaying discovery by almost two years. With the number of post menopausal estrogen and progestin prescriptions reduced to almost half, cancer rates have dropped by 7% in the year 2003.

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.