Up to 7 years of hormone therapy is safe for postmenopausal women, new data show


For decades now, women navigating menopause have been buffeted by shifting research findings on the risks and possible benefits of hormone-replacement therapy. Now, a landmark clinical trial that followed more than 27,000 subjects for roughly 18 years has offered some conclusive evidence that neither the hype nor the grim warnings about hormone-replacement therapy were warranted.

In findings published Tuesday in the journal JAMA, women who were randomly assigned to take some form of hormone-replacement therapy for a median of six to seven years were no more, nor less, likely to die of any cause over the study’s duration than were women who had been assigned to receive a placebo treatment.

The women who got synthetic estrogen and progesterone hormones to replace their naturally declining levels were no more (nor less) likely than those who got a placebo to die of stroke or heart failure. And they were neither more nor less likely to die of cardiovascular disease or cancer.

University of Pittsburgh Dr. Melissa McNeil, who wrote an editorial appearing alongside the new findings, called them “both compelling and reassuring.”

For women who enter menopause early, whose bones are at high risk of fracture, or who suffer menopause-related hot flashes, night sweats and sleep disruption, “hormone therapy appears to be both safe and efficacious,” wrote McNeil, who directs the comprehensive womens’ health program at Pitt’s general internal medicine division.

The findings come from the Women’s Health Initiative’s hormone therapy trials, which were launched to assess the benefits and risks to mostly healthy post-menopausal women of taking hormone-replacement pills in a bid to reduce their risk of developing such cardiovascular and other chronic diseases. The study’s 27,347 subjects averaged about 63 years old when they joined the study.

The Women’s Health Initiative has been the source of a number of findings on the safety of hormone replacement therapy, many of them more perplexing than enlightening. In 2002 and 2004, its findings raised concerns that HRT would increase women’s risk of heart disease, stroke and breast cancer.

Those findings would eventually lead to safer hormone combinations and a better understanding of who should consider HRT and when it should be initiated. But they would also slow a gathering stampede of menopausal women toward HRT and discourage many who could benefit from the treatment from considering it.

The latest trial results compared the death rates of 13,531 women who were assigned to take a placebo treatment to those of menopausal women who got one of two different forms of hormone-replacement therapy: 8,506 women — mostly those with an intact uterus — were assigned to get a combination of estrogen and progestin, and 5,310 — most of whom had undergone hysterectomy — got estrogen alone. (For women with an intact uterus, progestin was widely added to HRT regimens in the 1980s and ’90s after researchers found that estrogen-alone regimens increased rates of endometrial cancers in such women.)

Over the trial’s 18 years of follow-up, 7,489 of the women died. But whether researchers looked at death-from-any-cause, or deaths due to cancer, heart disease or stroke, the distribution of deaths in the trial’s various arms showed no statistically significant differences.

While those findings will probably reassure women who have avoided taking replacement hormones for menopausal symptoms, they are likely as well to temper claims that HRT can help women reduce their risk of certain diseases and prolong life.

The findings, the new study’s authors flatly wrote, “would not support use of hormone therapy for reducing chronic disease or mortality.”

The results of the new trial, which represents the largest and most comprehensive study to assess HRT’s effects, are in line with a position statement on HRT issued in June of this year by the North American Menopause Society.

That statement — the product of a comprehensive review of research by NAMS leaders — concluded that for most women who initiate hormone replacement therapy under 60, or within 10 years of reaching menopause, it’s safe and can improve quality of life, increase productivity and reduce medical expenditures linked to untreated symptoms of menopause.

“This study is just one more piece of reassuring data in line with our findings,” said Dr. JoAnn V. Pinkerton, professor of obstetrics and gynecology at the University of Virginia Health Center and chair of the NAMS panel that drafted that position statement.

In the wake of the first Women’s Health Initiative findings issued 15 years ago, said Pinkerton, “fear drove women’s decisions” on HRT. That should now change, she added — especially since safer and lower-dose HRT formulations are now available to women.

Pinkerton, who was not involved in the new research, acknowledged that women should not initiate hormone replacement therapy in hopes of fending off heart disease, dementia or osteoporosis. But despite the current study’s failure to find survival benefits in those who took HRT, Pinkerton said women who are considering treatment because they’re troubled by hot flashes and menopausal symptoms should know they might get some protection.

“There’s a critical window” during which other research suggests the initiation of hormone replacement “appears to have benefits for heart, brain and bone,” Pinkerton said.

Hormone Therapy Isn’t As Risky As Once Thought, New Study Finds


Scientific opinion on hormone replacement therapy sometimes feels like a pendulum that swings back and forth, leaving women confused about what treatment for menopause symptoms, including hot flashes, vaginal dryness and osteoporosis, is best for them.

While all medical treatments pose some risk, are the risks of treating menopause symptoms worth the benefits that hormone replacement therapy (HRT) can deliver? That’s the question that women have been asking and hoping that research clarifies.

Maybe it’s time for them to relax, a new study suggests.

In a new randomized study of 27,347 women who were followed for 18 years, those who took hormone medication were no more likely to die of any cause than women who were given a placebo.  

The Women’s Health Initiative hormone therapy trials tested the most common types of hormone therapy ― estrogen alone and estrogen plus progestin ― to assess the benefits and risks of menopause hormone therapy taken for chronic disease prevention by predominantly healthy postmenopausal women.

Researchers analyzed data from two trials, which included postmenopausal women with an average age of 63 at enrollment, and explored the effect of treatment over five to seven years, with 18 years of cumulative follow-up, and then defined the effect of hormone therapy on mortality rates. 

All-cause mortality provides a “critically important summary measure” for an intervention such as hormone therapy that has a complex matrix of benefits and risks, said lead author JoAnn E. Manson, a professor at Harvard Medical School and a past president of The North American Menopause Society.

“Mortality rates are the ultimate ‘bottom line’ when assessing the net effect of a medication on serious and life-threatening health outcomes,” she told HuffPost.

The team also found that deaths from Alzheimer’s disease and other forms of dementia were significantly lower with estrogen-alone medication than with a placebo during 18 years of follow-up.

Women and doctors should be reassured.

Hormone therapy, while unquestionably effective in reducing hot flashes and other menopause symptoms, has also been linked to serious health risks including blood clots, stroke and certain cancers. “In this new analysis, we found that there was no association between hormone therapy and all-cause mortality during either the treatment period or the long-term follow-up of these trials,” Manson said.

In this study, participants were assigned randomly to separate groups to compare different treatments. By using this randomization method, the groups were guaranteed to be similar and the treatments could be compared objectively. Other studies were conducted differently.

Manson said that her team’s findings support clinical guidelines that endorse the use of hormone therapy for recently menopausal women to manage hot flashes and other symptoms. 

Overall, she told HuffPost, the findings should reassure women and their doctors that hormone therapy is a reasonable option for symptomatic women who are in early menopause and in generally good health. 

Still, it is confusing to know which study is right.

For many women, just the act of processing all the seemingly conflicting findings on the value and risks of HRT can be confusing.

Many hark back to the 2002 Million Women Study in Britain, which shook women to the core when it proclaimed that HRT was potentially harmful and caused a higher risk of fatal breast cancer. 

A year after that study came another that linked taking estrogen plus progestin to an increased risk of dementia. That study, too, concluded the HRT combination presented risks that outweighed its measured benefits.

The multiple studies suggesting that potential harm outweighed the benefits of hormone therapy led to a swift decline of its use throughout Europe and the U.S.

Sales of hormone therapies fell by 50 percent from 2002 to 2005 as women got the message that HRT caused more problems than it solved. Increased risks of breast cancer, heart disease, stroke and blood clots were just some of the problems researchers documented in women who used HRT.

The medical community has modified its views about the role of hormones as more research has been conducted. Experts agree that there is much they still have to learn, said The North American Menopause Society. 

Joann Pinkerton, director of the NAMS, says the group recommends not limiting hormone therapy to the lowest dose or shortest duration but instead to find the most appropriate hormone therapy for each woman. 

There are many newer options, including transdermal patches, with potentially less risk of blood clots or stroke, she said.

The research was published Tuesday in JAMA.


Researchers Track an Unlikely Culprit in Weight Gain

From the NY Times - 

For middle-aged women struggling with their weight, a recent spate of scientific findings sounds too good to be true. And they may be, researchers caution.

Studies in mice indicate that a single hormone whose levels rise at menopause could be responsible for a characteristic redistribution of weight in middle age to the abdomen, turning many women from “pears” to “apples.” At the same time, the hormone may spur the loss of bone.

In mouse studies, blocking the hormone solves those problems, increasing the calories burned, reducing abdominal fat, slowing bone loss and even encouraging physical activity.

The notion that such a simple intervention could solve two big problems of menopause has received the attention of researchers and has prompted commentaries in prestigious journals like The New England Journal of Medicine and Cell Metabolism.

“It’s a super interesting idea,” said Dr. Daniel Bessesen, an obesity expert and professor of medicine at the University of Colorado School of Medicine. With obesity rising, “we definitely need some new ideas.”

The work began when Dr. Mone Zaidi, a professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, became curious about whether a reproductive hormone — F.S.H., or follicle-stimulating hormone — affects bone density.

It had long been assumed that the hormone’s role was limited to reproduction. F.S.H. stimulates the production of eggs in women and sperm in men.

Researchers knew that blood levels of F.S.H. soar as women’s ovaries start to fail before menopause. At the same time, women rapidly lose bone — even when blood levels of estrogen, which can preserve bone, remain steady.

Dr. Zaidi reasoned that F.S.H. could be a culprit in bone loss. So he and his colleagues created an antibody that blocked F.S.H. in female mice whose ovaries had been removed.

Since the mice were making no estrogen at all, they ought to have been losing bone. Indeed, the bone marrow in such mice usually  fills with fat instead of developing bone cells. Much the same happens in women: That’s why their bones become less dense.

But in Dr. Zaidi’s lab, the mice that received the antibody did not developed fat-filled bone marrow — and, to his enormous surprise, they lost large amounts of fat.

“This is a weird, weird finding,” he recalled telling his friend Dr. Clifford J. Rosen, a bone specialist at Maine Medical Center Research Institute. Dr. Zaidi persuaded Dr. Rosen to help repeat the experiments independently, each in his own lab.

At first, Dr. Rosen was dubious: “I said, ‘I don’t believe it, I think it’s not going to work, and it will cost a lot of money.’” But he received a grant for the research, and the two labs got started.

Two and a half years later, they had their results — and they replicated Dr. Zaidi’s original findings. The researchers also came up with a theory that might explain increased metabolic rates in mice in which F.S.H. is blocked.

There are two kinds of fat in the body: White fat primarily stores energy, and brown fat burns calories and throws off heat.

Brown fat is more common in children, but researchers have found that adults also carry small amounts. In the experimental mice, white fat was being converted to brown fat.

At the moment, Dr. Rosen is withholding judgment about whether the results will apply to humans. “I think the idea has some credibility,” he said. “But does it mean anything? I don’t know.”

But these are not the only researchers to find a link between obesity and the strange interplay of hormones.

Wendy Kohrt, a professor of medicine at the University of Colorado, has been studying the effects of menopause on women’s body fat and the amount of calories women burn.

Dr. Kohrt has given healthy premenopausal women a drug that blocks production of estrogen and F.S.H., putting them into a reversible state of menopause.

Within five months, she found, the women’s fat moves to their abdomens, increasing by 11 percent on average. And they burn 50 fewer calories per day.

The effect is reversed when the participants stop taking the drug or when Dr. Kohrt gives them estrogen.

Something similar goes on in men, although it’s not clear that F.S.H. is the sole cause, said Dr. Michael W. Schwartz, director of the Nutrition Obesity Research Center at the University of Washington.

Men with advanced prostate cancer often take Lupron, a drug intended to stop the production of testosterone, which can fuel their tumors. Often, they gain weight, accumulating fat in their abdomens.

Lupron also blocks production of F.S.H., and the mouse studies suggest that this should prevent weight gain. That might be because of the loss of testosterone.

Yet in experiments in which men were given both Lupron and testosterone — leaving F.S.H. the only blocked hormone — they still did not lose weight. F.S.H. clearly is not the only factor at work, then.

But the dream of an easy way to prevent abdominal weight gain is so appealing, you just want it to be true, said Dr. Philipp E. Scherer, a professor of internal medicine at the University of Texas Southwestern Medical Center.

He has seen too many mouse studies fail in humans to be persuaded that this one will succeed. “I will be on the sidelines waiting,” he said.

Dr. Zaidi is undeterred. He is already preparing to test an anti-F.S.H. antibody in people.

“Whether it works in humans, I have absolutely no idea,” Dr. Zaidi said.