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.”

Hormone Replacement Therapy (HRT) Improves Sleep, Sexuality and Joint Pain in Older Women

The British Medical Journal has just published the findings of new study by the WISDOM research team (Women’s International Study of long Duration Oestrogen after Menopause) which finds that HRT therapy can achieve major improvements in quality of life.

The average age of the 2,130 post-menopausal women used for the study was 13 years after menopause (although most of them did not have menopausal symptoms). Participants lived in the UK, Australia and New Zealand, and the study measured the impact on their quality of life of combined oestrogen and progestogen hormone therapy.

“Our results show that hot flushes, night sweats, sleeplessness and joint pains were less common in women on HRT in this age group. Sexuality was also improved,” says Professor Alastair MacLennan, leader of the Australian arm of WISDOM and head of Obstetrics & Gynaecology at the University of Adelaide, Australia. Overall, quality of life measures improved. Even when women did not have hot flushes and were well past menopause, there was a small but measurable improvement in quality of life and a noted improvement in sleep, sexuality and joint pains. HRT users also had more breast tenderness and discharge compared to those on a placebo,” he says.

Dr. Beverley Lawton, Head of WISDOM New Zealand, says: “These new data should be added to the risk/benefit equation for HRT. The quality of life benefits of HRT may be greater in women with more severe symptoms near menopause. New research suggests that HRT taken from near menopause avoids the cardiovascular risks seen when HRT is initiated many years after menopause.”

Professor MacLennan says studies such as those conducted by WISDOM “enable the risks of HRT to be reduced and its benefits maximized when the treatment is individualized to each woman”.
“Early start-up side effects can usually be alleviated by adjusting the treatment,” he says. “For most women with significant menopause symptoms the benefits of HRT outweigh the risks.

The latest analyses of the main long-term randomized control trial of HRT (The Women’s Health Initiative) show that breast cancer is not increased by oestrogen-only HRT and is only increased in women using combined oestrogen and progestogen HRT after seven years of use. This increased risk is less than 0.1% per year of use.

“If a woman feels that HRT is needed for quality of life, then doctors can find the safest regimen for her. She can try going off HRT every 4-5 years, and can then make an informed choice about whether she takes and continues HRT.”

Source: British Medical Journal, Augst 22, 2008 (BMJ 2008;337:a1190)

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

Cardiologists Call for New Approach in Treating Chest Pain

In a joint statement by the American College of Cardiology (ACC) and the American Heart Association (AHA), physicians are calling for a more aggressive approach to evaluating patients presenting with chest pain (unstable angina)—and quickly determining whether the therapeutic approach should be medical, invasive or a combination of two.

Guidelines released today by the ACC encourage the early use of tests such as a stress test, an echocardiogram or a radionuclide angiogram (which visualizes the coronary arteries) in patients considered stable.

Cessation of smoking, lowering blood pressure, and lowering cholesterol are all part of the effort to lower the risk of heart attack.

The new guidelines call for an LDL cholesterol to be lower than 100 mg/dL, with a target number of 70 mg/dL. Blood pressure should be lower than 140/90.

A significant new recommendation is the guideline to cease prescribing hormone replacement therapy (HRT) for post-menopausal women.

Menopause Pill Pristiq Fails to Get FDA Approval

The Federal Drug Administration (FDA), in its letter to Wyeth—the manufacturer of the menopause Pill Pristiq—has outlined the need to perform at least one more year of clinical tests on the drug before it is aproved.

The FDA has called for more data on how Pristiq affects the heart and liver health of patients.
Wyeth, which is the largest manufacturer of hormone treatments today, has developed Pristiq to control menopausal symptoms such as night sweats and hot flashes and has forecast an annual revenue of $2 billion from the drug.

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) 

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.