Extended follow-up of hormone therapy trials does not support use for chronic disease prevention

Extended follow-up of the two Women's Health Initiative hormone therapy trials does not support use of hormones for chronic disease prevention, although the treatment may be appropriate for menopausal symptom management in some women, according to a study in the October 2 issue of JAMA.

01 oct 2013--The hormone therapy trials of the Women's Health Initiative (WHI) were stopped after investigators found that the health risks outweighed the benefits. Menopausal hormone therapy continues in clinical use, but questions remain regarding its risks and benefits over the long-term for chronic disease prevention, according to background information in the article.

JoAnn E. Manson, M.D., Dr.P.H., of Brigham and Women's Hospital, Boston, and colleagues provide a comprehensive, integrated overview of findings from the two WHI hormone therapy trials with extended post-intervention follow-up and stratification by age and other important variables. The study included 27,347 postmenopausal women, ages 50 through 79 years, who were enrolled at 40 U.S. centers in 1993. Women with an intact uterus received conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) (n = 8,506) or placebo (n = 8,102). Women with prior hysterectomy received CEE alone (n = 5,310) or placebo (n = 5,429). The intervention lasted a median [midpoint] of 5.6 years in the CEE plus MPA trial, and 7.2 years in the CEE alone trial, with 6-8 additional years of follow-up until September 30, 2010.

The researchers found that overall, the risks of CEE+MPA during intervention outweighed the benefits. Risks were increased for coronary heart disease, breast cancer, stroke, pulmonary embolism, dementia (in women 65 years of age and older), gallbladder disease, and urinary incontinence. Benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during follow-up.

For CEE in women with prior hysterectomy, the benefits and risks during the intervention phase were more balanced, with increased risks of stroke and venous thrombosis, reduced risk of hip and total fractures, and a nonsignificant reduction in breast cancer. Post-intervention with CEE, a significant decrease in breast cancer emerged and most other outcomes were neutral. For CEE alone, younger women (age 50-59 years) had more favorable results for all-cause death and heart attack.

Neither regimen affected all-cause mortality.

"In summary, current WHI findings based on results from the intervention, postintervention, and cumulative posttrial stopping phases do not support the use of either estrogen-progestin or estrogen alone for chronic disease prevention," the authors write.

"Even though hormone therapy may be a reasonable option for management of moderate to severe menopausal symptoms among generally healthy women during early menopause, the risks associated with hormone therapy, in conjunction with the multiple testing limitations attending subgroup analyses, preclude a recommendation in support of CEE use for disease prevention even among younger women. Current findings also suggest caution when considering hormone therapy treatment in older age groups, even in the presence of persistentvasomotor symptoms, given the high risk of coronary heart disease and other outcomes associated with hormone therapy use in this setting."

"Twenty-two years following its inception, the WHI is a model for publicly funded rigorous, thorough, and objective clinical trials that have broadly affected human health. More than 160,000 women participated (many with great pride), more than 900 peer-reviewed reports from the WHI Publications and Presentations Committee have been published, the WHI data set is publically available, and scores of trainees have been mentored in fields from human biology to public health by participating in its analysis. The WHI has overturned medical dogma regarding the use of menopausal hormone therapy," writes Elizabeth G. Nabel, M.D., of Brigham and Women's Hospital, Boston, in an accompanying editorial.

"The WHI underscores the decisive importance of taxpayer-funded research conducted by the National Institutes of Health (NIH). Further reductions in the NIH budget virtually ensure that vitally important studies like the WHI will not be conducted, and hence, U.S. society will be poorly served. The fact that the public sector undertook this historic project (and that the researchers whose work is now reported have taken it to its next stage) has moved medical science forward by the most effective means of doing so—shattering prior dogma. For that,women and all patients whose health depends on sound science are grateful."

More information: doi:10.l001/jama.2013.278040
doi:10.l001/jama.2013.278042

Provided by The JAMA Network Journals

15 top medical organizations agree on hormone therapy use

After 10 years of debate regarding the risks and benefits of hormone therapy, 15 top medical organizations have come together to issue a statement of agreement regarding the benefits of hormone therapy for symptomatic menopausal women. It was July 9, 2002, when the controversial, highly publicized Women's Health Initiative (WHI) published its assessment of hormone therapy for the prevention of chronic disease and concluded that risks exceeded benefits. The new joint statement, prepared by The North American Menopause Society (NAMS), the American Society for Reproductive Medicine (ASRM), and The Endocrine Society, concludes that hormone therapy is still an acceptable treatment for menopausal symptoms. This statement has been endorsed by 12 other leading organizations in women's health.

10 july 2012--The purpose of this statement is to reassure women and their providers that hormone therapy is acceptable and relatively safe for healthy, symptomatic, recently postmenopausal women. Over the last 10 years, there has been a complete abandonment of hormone therapy in some settings accompanied by reluctance to treat women who would benefit from relief of their symptoms. As a result, some women have sought unproven alternative therapies.

"We believe that too many symptomatic women are missing out on the proven benefits of hormone therapy because the results of the WHI, which studied the long-term use of hormones to prevent chronic disease, were misinterpreted for women with menopausal symptoms" said Dr. Margery Gass, Executive Director for NAMS. "Women and clinicians are frustrated by the many conflicting recommendations. That's why we initiated this effort to bring these notable medical organizations together in agreement regarding the use of hormone therapy."

Roger Lobo, MD, Past President of the American Society for Reproductive Medicine added, "Physicians can help patients determine, based on their own particular characteristics and history, whether or not they are good candidates for hormone therapy and what type of HT will provide them the greatest relief at the lowest risk. A decade of research and analysis has shown us that the generalized conclusions of the WHI do not apply to younger women at the beginning of the menopausal transition."

"The results of the WHI and the conflicting reports that followed led many women to believe hormone therapy may not be a safe treatment for menopausal symptoms," said Janet E. Hall, MD, immediate Past President of The Endocrine Society. "We want women to know that there are options out there for relief of their menopausal symptoms. The level of risk depends on the individual, her health history, age, and the number of years since her menopause began."

When it comes to the safety and effectiveness of hormone therapy, one commonly heard lament is, "Even the experts don't agree." This statement was prepared to address this misperception by presenting evidence-based key concepts about hormone therapy to assist women and their clinicians in making informed decisions about use of hormone therapy when appropriate.

Major points of agreement among the societies include: 

• Hormone therapy is an acceptable option for the relatively young (up to age 59 or within 10 years of menopause) and healthy women who are bothered by moderate to severe menopausal symptoms. Individualization is key in the decision to use hormone therapy.
• If women have only vaginal dryness or discomfort with intercourse, the preferred treatments are low doses of vaginal estrogen.
• Women who still have a uterus need to take a progestogen (progesterone or a similar product) along with the estrogen to prevent cancer of the uterus. Women who have had their uterus removed can take estrogen alone.
• Both estrogen therapy and estrogen with progestogen therapy increase the risk of blood clots in the legs and lungs, similar to birth control pills, patches, and rings. Although the risks of blood clots and stroke increase with either type of hormone therapy, the risk is rare in women ages 50-59.
• An increased risk in breast cancer is seen with 5 or more years of continuous estrogen with progestogen therapy, possibly earlier. The risk decreases after hormone therapy is stopped.

Provided by The North American Menopause Society (NAMS)

The Women's Health Initiative: An unforgettable decade

The 10-year anniversary of the historic Women's Health Initiative (WHI) Hormone Therapy Trial report, which radically changed the practice of women's health, will be commemorated in July 2012. In anticipation of this event, two of the world's leading experts in women's health, menopause, and hormone therapy are releasing an editorial in the journal Menopause, providing their perspective on this epic study and the lessons learned over the past 10 years.

01 jun 2012--JoAnn Manson, MD, MPH, DrPH, from Brigham and Women's Hospital (BWH), and Lubna Pal, MBBS, MRCOG, MSc, from Yale University School of Medicine, note that the WHI's 10-year anniversary is a good time to reflect on the pendulum swings and dramatic evolution in our thinking about estrogen and hormone therapy (HT), which changed the lives of millions of women. The authors state in their editorial, "The WHI is an historic trial that has changed clinical practice and, ultimately, has helped lead us towards a more rational interpretation of the place of hormone therapy in menopause management."
The WHI hormone trials were designed to assess the role of HT in the prevention of heart disease, as well as to evaluate the benefits and risks of HT when used for chronic disease prevention. The trials were done in postmenopausal women ages 50-79 (with a mean age of 63) and tested the types of HT (Premarin and Prempro) that were in common use at the time the study started. The estrogen plus progestin trial was stopped three years early because of an increased risk of breast cancer, heart disease, and concerns that the overall risks exceeded the benefits. The estrogen-alone trial (in women with hysterectomy) showed fewer risks but was stopped one year early due to an increased risk of stroke. Estrogen-alone did not appear to increase risk of heart disease or breast cancer. In fact, estrogen-alone seemed to lower the risk of heart disease in younger women (in the 50-59 year age group) and seemed to have a favorable benefit-risk profile in that age group. However, the harmful findings in the older women in both HT trials tended to be extrapolated to younger women, resulting in dramatic (>70%) reductions in prescriptions for hormone therapy.
Manson, one of the principal investigators of the WHI since the start of the study and current president of the North American Menopause Society, said, "The WHI deserves credit for stopping the growing clinical practice of prescribing hormone therapy to older women who were at very high risk of heart disease. In fact, these women did not receive heart benefit from estrogen therapy and may even have suffered harm. Unfortunately, the findings in older women were extrapolated to newly menopausal healthy women who tended to have a favorable benefit to risk ratio with HT."
At least 70% of newly menopausal women have hot flashes and/or night sweats, and about 20% have moderate-to-severe symptoms that disrupt sleep and impair quality of life. Over the past 10 years, research from the WHI and other studies has provided a critical mass of evidence for the timing hypothesis, which suggests that younger women closer to the onset of menopause tend to have better outcomes on hormone therapy than older women who are distant from menopause onset. The younger women are also more likely to have hot flashes and other menopausal symptoms, and thereby derive quality of life benefits. Manson said, "The recent findings highlight the importance of individualized care for women. The 'one size fits all' approach to decision making is no longer acceptable." Manson adds that it will also be important to understand whether different types and formulations of hormone therapy (such as patches, pills or lower doses of hormones) will have a different balance of benefits and risks.
Provided by Brigham and Women's Hospital

USPSTF recommends against hormone therapy

 

NEW YORK, 31 may 2012--- Women taking hormone replacement therapy face a complicated mix of possible benefits and risks, a new meta-analysis confirms.

The analysis, published Monday in the Annals of Internal Medicine, combines the results of nine previous clinical trials and found that women taking estrogen or a combination of estrogen and progestin lowered their risk of fracture, but increased their risks for a host of other complications, including strokes and gallbladder disease.
Taken together, estrogen and progestin also seemed to increase the risk of breast cancer and dementia -- although estrogen alone was tied to fewer breast cancer cases.
Based on the new analysis, the government-backed U.S. Preventive Services Task Force (USPSTF) issued preliminary recommendations on Tuesday that postmenopausal women not use hormone therapy to prevent certain chronic conditions.
The Women's Health Initiative study, sponsored by the U.S. National Institutes of Health, showed in 2002 that postmenopausal women taking combination hormone therapy had a higher risk of heart disease and certain cancers.
After that, the USPSTF recommended against the combined use of estrogen and progestin to prevent chronic conditions, and later did the same for estrogen alone in 2005. Their new recommendations do not change that.
The lead author of the new analysis done for the USPSTF said although women have heard a lot about the possible risks and benefits of hormone therapy, there hasn't been a clear message about hormone use.
"We looked at what we could find in this area and tried to find the most final results at this time," said Dr. Heidi Nelson, from Oregon Health & Science University in Portland.
The new recommendations, according to the USPSTF, are based on a "moderate to high certainty that the service has no benefit or that the harms outweigh the benefits."
Dr. Nelson and her team searched the medical literature and found nine randomized controlled trials that fit their standards and were published since 2002.
Four of the studies drew their conclusions from the two Women's Health Initiative trials on hormone therapy, which followed over 27,000 women. In those studies, one group took estrogen, another took estrogen and progestin and the other two took placebos.
Both trials were stopped short because the increased side effects tied to the drugs outweighed their benefits.
Overall, the researchers found women taking combined progestin and estrogen and women taking estrogen alone were 25 to 30% less likely to suffer a fracture during the studies compared to the women taking a placebo.
That worked out to about five fewer broken bones per every 1,000 women annually when they were on hormone therapy.
Women taking those hormones, however, had a 34% to 79% higher chance of having a stroke, gallbladder disease or urinary incontinence. Both combination and estrogen-only treatment were also tied to more cases of "probable" dementia.
And the risk of invasive breast cancer was 25% higher in the estrogen-plus-progestin group than in the comparison group not on hormonal therapy -- but 23 percent lower among those just on estrogen.
Finally, blood clots were about twice as common in women taking combined hormone therapy than in the placebo group.
"The biggest harms are still there," said Dr. Nelson, comparing the results to earlier findings. "We're talking about blood clots and stroke. Those things were there initially and those things have not changed."
The researchers note their conclusions are only based on a few trials, and although those trials followed a lot of women, many stopped taking the hormones during the trial. And the information is also limited to women between the ages of 60 and 69 years old.
The new USPSTF recommendations will be available for review and public comment on the panel's website until June 26.

SOURCE: http://bit.ly/KXHgHH

Hormone therapy linked to increased cancer risk

WASHINGTON, 22 oct 2010 – Menopausal women taking combined hormone therapy have an elevated risk of being diagnosed with a more advanced stage of breast cancer and dying from it, according to a new US study.

Researchers conducted a new analysis of a landmark, federally funded clinical trial known as the Women's Health Initiative (WHI), which was halted in 2002 after data suggested women who took a combination of estrogen and progestin hormones faced a higher risk of breast cancer.

The study, published in this week's edition of the Journal of the American Medical Association, also found that women who previously used hormone therapy and discontinued it after the WHI was terminated still faced a slightly higher breast cancer mortality rate than women not taking hormones.

For their analysis, Rowan Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and colleagues observed 16,608 postmenopausal women ages 50 to 79 years with no prior hysterectomy from 40 US clinical centers.

Their follow-up of about 11 years of WHI participants found that 385 women receiving hormones for an average of 5.6 years, or 0.42 percent, developed invasive breast cancer, compared with 293 women who received a placebo, or 0.34 percent.

A significantly larger fraction of the women in the hormone therapy group -- 81, or 23.7 percent -- were diagnosed after their breast cancer had spread to lymph nodes. In the placebo group, only 43 women, or 16.2 percent, were diagnosed at that stages.

Twenty-five of the women who received the hormone therapy died from breast cancer, compared to 12 deaths among those who received a placebo. That translated to one to two extra deaths from breast cancer each year for every 10,000 women who used hormone therapy rather than a placebo.

Researchers noted that in the WHI trial, unlike most observational studies, combined hormone therapy both increased the risk of breast cancer and interfered with breast cancer detection, hindering the detection of breast cancer and thus leading to diagnoses at more advanced stages.

"Now, with longer follow-up results available, there remains a cumulative, statistically significant increase in breast cancers in the combined hormone therapy group, and the cancers more commonly had lymph node involvement," the researchers said.

"The observed adverse influence on breast cancer mortality of combined hormone therapy can reasonably be explained by the influence on breast cancer incidence and stage."

They noted that the incidence of breast cancer substantially decreased in the United States after the WHI trial's results were initially reported eight years ago, which was attributed to a marked decrease in postmenopausal hormone therapy use.

"The adverse influence of estrogen plus progestin on breast cancer mortality suggests that a future reduction in breast cancer mortality in the United States may be anticipated as well," the researchers added.

In an accompanying editorial, Peter Bach of Memorial Sloan-Kettering Cancer Center in New York said "the available data dictate caution in the current approach to use of hormone therapy," namely because physicians are "ill-equipped" to anticipate its effects on long-term health.

"Clinicians who prescribe brief courses of hormone therapy for relief of menopausal symptoms should be aware that this approach has not been proven in rigorous clinical trials and that the downstream negative consequences for their patients are of uncertain magnitude," Bach added.

Dense Breasts + Hormones Up Cancer Risk After Menopause

Breast cancer risk particularly increased with estrogen plus progestin

21 july 2010-- Postmenopausal women with high breast density, especially those undergoing hormone therapy with estrogen plus progestin, are at higher risk for developing breast cancer, according to a study published online July 19 in the Journal of Clinical Oncology.

Karla Kerlikowske, M.D., of the California Pacific Medical Center Research Institute in San Francisco, and colleagues evaluated data on 587,369 women who underwent 1,349,027 screening mammography exams. Breast cancer was diagnosed among 14,090 women. The researchers used a survival model to determine five-year breast cancer risk for subgroups of women classified by their Breast Imaging Reporting and Data System (BIRADS) breast density, menopausal status, age, and current hormone therapy use, assuming a body mass index of 25 kg/m².

The researchers found that, among women aged 55 to 59 years with low breast density (BIRADS-1), the five-year breast cancer risk was 0.8 percent for those not using hormone therapy and 0.9 percent for those using estrogen and estrogen plus progestin. Among women aged 55 to 59 years with very high breast density (BIRADS-4), the five-year breast cancer risk was 2.4 percent for those not using hormone therapy, 3.0 percent for those using estrogen, and 4.2 percent for those using estrogen plus progestin. Compared to those with average breast density (BIRADS-2), risk of advanced-stage breast cancer was 1.7-fold higher for postmenopausal women using hormone therapy who had BIRADS-4.

"Approximately 50 percent of postmenopausal women have high or very high breast density, are at high breast cancer risk, and may be considering or using hormone therapy. Postmenopausal women with high breast density may want to consider the added risk of breast cancer when deciding on whether to start or stop hormone therapy, especially estrogen plus progestin," the authors conclude.

One author disclosed financial ties to Eli Lilly.

Abstract
Full Text (subscription or payment may be required)

WHI data confirm short-term heart disease risks of combination menopausal hormone therapy

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.

23 feb 2010--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.

The study is in the Feb. 16, 2010, Annals of Internal Medicine. The WHI is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH).

"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.

To interview Dr. Rossouw, call the NHLBI Communications Office at (301) 496-4236 begin_of_the_skype_highlighting (301) 496-4236 end_of_the_skype_highlighting or email NHLBI_News@nhlbi.nih.gov. To speak with Dr. Toh, please contact David Cameron, Office of Communications and External Relations at Harvard Medical School, at (617) 432-0441 begin_of_the_skype_highlighting (617) 432-0441 end_of_the_skype_highlighting.

For more information:

• NHLBI news release, March 4, 2008: WHI Follow-Up Study Confirms Risk of Long-Term Combination Hormone Therapy Outweigh Benefits for Postmenopausal Women, http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2554
• NHLBI Media Availability, April 7, 2007: Effect of Hormone Therapy on Risk of Heart Disease May Vary by Age and Years Since Menopause -- Additional Analyses from the Women's Health Initiative, http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=255
• Women's Health Initiative (http://www.nhlbi.nih.gov/whi)
• WHI Estrogen-Plus-Progestin Study (http://www.nhlbi.nih.gov/whi/estro_pro.htm)
• Menopausal Hormone Therapy Information (NIH) (www.nih.gov/PHTindex.htm)
• The Healthy Heart Handbook for Women (http://www.nhlbi.nih.gov/health/public/heart/other/hhw/index.htm)

Halting Hormone Therapy Reduces Breast Cancer Risk Quickly

06 feb 2009--Six years after a landmark federal study established that hormone-replacement therapy (HRT) increases the risk of breast cancer in postmenopausal women, researchers are still trying to tease out exactly how the hormones interfere with women's health. The assumption has always been that stopping hormone therapy would lead to a corresponding drop in breast-cancer risk, but now newly published data from the original trial - the multiyear Women's Health Initiative involving tens of thousands of women - suggest that the benefit occurs much more immediately than previously thought.

The finding is a contentious one. The authors of the new paper, which appears in the Feb. 5 issue of the New England Journal of Medicine, found that the rate of breast cancer in postmenopausal women fell just two years after they stopped hormone therapy and continued to decline yearly. In addition, researchers found that women taking supplemental estrogen and progestin had doubled their risk of breast cancer after five years, compared with women not taking HRT.

The question is why. The authors hypothesize that the decline in breast cancer rates was largely due to the sudden stoppage of hormone therapy. But this correlation, first presented at the San Antonio Breast Cancer Conference in December, has been met with skepticism by other researchers in the community. They raised concerns about drawing a cause-and-effect relationship, since the sharpest decline in women's breast cancer rates occurred in the year after the WHI was halted and its data released, between 2002 and 2003 - too soon to see such a dramatic change in a complex disease like breast cancer, which takes many years to develop.

Samuel Shapiro, a visiting professor of epidemiology at University of Capetown, notes that any cancers that might have existed in breast tissue when these women stopped hormone therapy would not have simply disappeared post-treatment. "Once the growth of a tumor has accelerated, it can't be decelerated," he says. "I'm not aware of any evidence to show that happens."

Dr. Roman Chelbowski, lead author of the current study and a medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, disagrees. He says the rapid decline in cancer rates was due not only to an overall drop in breast-cancer risk, but also to the withdrawal of excess estrogen, which may actually have served as a treatment for tiny, preclinical breast cancers. "When you change from a high- to a low-estrogen environment, it's like giving breast cancer treatment," he says. "These are preclinical cancers that are below the level of detection, and that accounts for why biologically we can see such a quick effect in stopping hormone therapy." In the three-year WHI study alone, there were 20,000 preclinical breast cancer cases among the women who continued taking hormone therapy - cancers that may potentially have been avoided.

"That is a reasonable and biologically plausible explanation for why we might be seeing a more precipitous drop in breast cancer than we might expect from the normal lead time for reduction of malignancies," says Dr. Jonathan Berek, chair of obstetrics and gynecology at Stanford University School of Medicine, who was not involved in the study.

Berek notes that while breast cancers do generally grow for a decade or more before becoming detectable, cancer is a tricky disease that constantly tests our expectations. "Nobody understands this disease that well, and maybe what this study is telling us is that the biology of these estrogen-dependent cancers is not quite what people thought it was."

And although the academic back-and-forth over what caused an undeniably good health trend - a reduction in breast cancer - might seem superfluous, the study does reaffirm an important message for women: Hormone use at menopause does increase the risk of breast cancer, so estrogen and progestin should be used for the shortest possible time, only to relieve menopausal symptoms. "This study isn't an indictment of hormone use at menopause," says Berek. "It just means that like all medicines, hormones have their benefits and risks, so they have to be used very judiciously and for a short time."

Estrogen therapy could be dangerous for women with existing heart risk

ANN ARBOR, Mich., 27 nov 2008---Hormone therapy could accentuate certain pre-existing heart disease risk factors and a heart health evaluation should become the norm when considering estrogen replacement, new research suggests.
The research also showed that in women without existing atherosclerosis, hormone therapy use included some positive effects on lipids but also some negative effects related to heart health, said MaryFran Sowers, lead researcher and professor of epidemiology at the University of Michigan School of Public Health.
The U-M study came about, Sowers said, in trying to explain what's behind the so-called timing hypothesis. The timing hypothesis suggests that if a woman implements a hormone therapy program within six years of her final menstrual period, this narrow window is enough to deter heart disease from developing with the onset of menopause. But the U-M findings suggest that explanation isn't quite so simple, Sowers said.
Even within the six-year window, there were negative aspects related to heart disease. While the positive outcomes on HDL and LDL cholesterol levels were observed, Sowers said, researchers also saw negative outcomes in terms of the inflammation process---which can be related to heart disease.
Sowers said the research shows it's critical for women considering hormone therapy to discuss their heart health with their doctor.
"If the woman walks into the doctor's office with a certain degree of (heart disease) burden already, then she and her health care provider may decide that hormone therapy adds too much to the burden," Sowers said. "If she doesn't have that burden, they may decide that hormone therapy is an acceptable burden.
"The woman should say to her health care provider, 'What kind of information do we need to gather in order to make an informed decision about whether or not hormone therapy should be pursued,'" Sowers said. '"I understand there could be some heart disease risk, but that the risk may be based upon where I am now, and can you tell me where that is?'"
Heart disease risk can be measured through lipid panels, which are standard, but also by measuring inflammation markers, Sowers said. Tests for inflammation markers exist but their measurement isn't standard when a women is considering hormone therapy, Sowers said.
Hormone therapy has been controversial for years, and there was a time when there was an almost knee jerk reaction against it, Sowers said. This backlash occurred after the findings from the Women's Health Initiative study showed that some women on estrogen therapy had increased heart disease risk. The six-year timing hypothesis was an attempt to explain the findings in the WHI study, Sowers said.

Hormone Therapy Given Closer to Menopause Onset Is Safest

April 7, 2007 — There is new evidence that timing of initiation of hormone therapy (HT) may determine the extent of its cardiovascular effects, this time from a new analysis of the Women's Health Initiative (WHI) randomized controlled trials. The study suggests that coronary heart disease (CHD) risk associated with hormone therapy is not significantly increased in women who take hormone therapy within 10 years of the onset of menopause, and even showed a trend toward reduced CHD risk, but that this risk increases if women start taking hormone therapy after a longer gap. Risk for stroke, however was increased at any time point postmenopause.
Lead author Jacques E. Rossouw, MD, from the National Heart, Lung, and Blood Institute in Bethesda, Maryland, emphasized to heartwire that the findings should be viewed as "reassuring" for younger women with moderate to severe menopause symptoms who have worried about the risks of starting hormone therapy. The study should not, however, be viewed as supporting any role for hormone therapy to reduce cardiovascular events.
"This analysis should be appreciated mainly for the somewhat positive message for the short-term use of hormone therapy for menopausal symptoms," he said. "For those women who were afraid to use it before, there's some encouragement here that it might be a reasonable thing to do in the short term. But it doesn't change anything about our overall recommendations, that is, you don't use hormone therapy for the prevention of heart disease at any age."

Health Risk to Older Women Is Seen in Hormone Therapy

A new analysis of combined data from two parts of a large federal study of hormone therapy has found that women in their 50s do not appear to have an increased heart attack risk if they take the drugs. But it also found that women in their 60s and 70s who still had hot flashes and night sweats were at increased risk for heart attacks, even if they were not taking hormones. And if these women took hormone therapy, their risk was higher still.
“The main indication now for hormone therapy is hot flashes and night sweats,” said Dr. Jacques Rossouw, a researcher for the National Heart, Lung and Blood Institute who directed the federal study, the Women’s Health Initiative. “This says that if you are older than 60, you should not take it.”

Updated Statement on Hormone Therapy

February 1, 2007 — A scientific advisory panel to the North American Menopause Society has issued a position statement on the use of hormone therapy (HT), which softens its previous stance on the issue. The statement was published in the February 25 Ahead of Print issue of Menopause.
"For women with severe menopausal symptoms, within a few years of their last period, hormone therapy shouldn't be as scary as it has been made out to be," director of the North American Menopause Society and panel chair Wulf Utian, MD, PhD, of Case Western Reserve University in Cleveland, Ohio, told heartwire.
For older women, the decision is more difficult, he says. Although there are fewer women of this age who will require HT, some have menopausal symptoms for many years or have experienced symptoms after stopping HT in the past few years, and this group wants to know whether they can restart therapy. But older women are at higher absolute risk for cancer and heart disease, so "it has to be a personal decision, our panel is stating that very clearly. An older woman must consider all the risks and benefits."