University of Virginia Health System

Estrogen Mimic May Prove Safer Bone Builder

Molecule avoids downsides of hormone therapy

< November 12, 2002 > A synthetic version of estrogen may provide all of the bone-preserving benefits of the hormone without any harmful effects on the reproductive system, new research has found.

Treatment with the substance, called estren, increased bone density and bone strength in female mice deprived of estrogen by removal of their ovaries. It was also effective in male rodents lacking testosterone.

Better yet, the compound seems to be invisible to cells in the uterus and breast, where estrogen is known to trigger cancers.

The value of hormone replacement therapy (HRT), often prescribed to combat osteoporosis, has been called into question over recent discoveries that its benefits may outweigh its risks.

Estren is not a hormone, but its molecular structure is close enough to estrogen's that it fits cellular receptors specific to the sex steroid, says study leader Dr. Stavros Manolagas, director of the Center for Osteoporosis and Metabolic Bone Diseases in Little Rock, Ark.

Manolagas and his colleagues reported their findings last month in Science.

More than eight million American women suffer from osteoporosis, putting them at significant risk of painful and debilitating fractures. The bone-thinning disease also occurs in about two million men, and another 18 million or so people have weakened skeletons that predispose them to osteoporosis.

HRT has been in scientific limbo lately. Researchers last May halted a major government-funded trial of one form of hormone supplements, estrogen and progestin, after determining that its benefits, which included fewer fractures, did not outweigh the risk of rare but serious side effects, including heart trouble and breast cancers. Another arm of the trial looking at estrogen therapy alone is continuing.

In the latest study, Manolagas' group imbedded slow-release pellets of estren under the skin of female and male mice, then measured several qualities of the animals' bones over time. To simulate the effects of menopause, during which estrogen levels plummet, some of the female rodents had their ovaries removed.

The pellets led to bone formation and strength that was at least as impressive as that of rodents with normal estrogen levels, the researchers say. This effect on the skeleton was identical to that of treatments with a version of testosterone—another bone-forming hormone—in male mice missing their testicles.

Estren spurred the formation of bone-building cells called osteoblasts, which estrogen typically does not do, and led to substantially wider bones than in mice given estrogen. The ability of bones in the estren-treated mice to withstand compression was greater than that of the female animals receiving estrogen, and similar to that of male mice that received testosterone.

Estren's transparency to reproductive cells skirts the breast cancer problem, Manolagas says. Whether it might interfere with heart health "is the $6 billion question," he says, adding the researchers have not fully explored the toxicity of the molecule.

Estren, which is still experimental, would not be the only drug designed to mimic the best of estrogen while minimizing its potential side effects. A family of drugs called selective estrogen receptor modulators (SERMs), such as raloxifene, is currently being used to thwart osteoporosis.

Dr. Eric Orwoll, a bone specialist and director of the General Clinical Research Center at Oregon Health Sciences University in Portland, calls the new study "promising in two ways."

First, it helps flesh out the mechanics of sex hormones. And, it provides hope for a new addition to the treatments for osteoporosis, Orwoll says.

However, he adds that it is not entirely clear that estren's effects are so distinct from those of estrogen or SERMs. "What we don't understand is exactly how sex steroids do work in bone. Maybe sex steroids utilize this mechanism as well," he says.

Despite HRT's current tribulations, Manolagas says women will need the treatment.

"Estrogen replacement affects half the population of the earth for over 40 percent of their life," he says. "Women are going to be living 40 percent of their life without the hormones that made them women. Until 100 years ago, life expectancy and menopause were coinciding."

Always consult your physician for more information.

Online Resources

(Our Organization is not responsible for the content of Internet sites.)

National Institute of Arthritis and Musculoskeletal and Skin Diseases

National Institutes of Health Osteoporosis and Related Bone Disease - National Resource Center

National Institute of Neurological Disorders and Stroke

National Osteoporosis Foundation

For more information on osteoporosis, please visit the Orthopaedics information module on this Web site.

For more information on Alzheimer's disease, please visit the Nervous System Disorders information module on this Web site.

Long-Term Hormone Therapy No Help for Alzheimer's

In a study of rats, it made memory worse

Long-term hormone therapy, taken in the traditional continuous manner, does not improve symptoms of Alzheimer's disease in women and may make memory loss worse, a new rat study suggests.

The findings reflect those of a human study, published in 2000 in the Journal of the American Medical Association (JAMA), in which researchers found that women with mild to moderate Alzheimer's who were put on hormone replacement therapy initially had better mental functioning than women with the disease who were not on the therapy. However, then the hormone-supplemented group's mental skills dropped below that of the women not on the therapy.

Hormone therapy "is seen as a neuroprotective agent," says Gary L. Wenk, a researcher at the University of Arizona.

His team found otherwise, at least when the therapy was given continuously.

For the study, published in the October issue of Behavioral Neuroscience, the researchers induced ovarian failure in female rats and produced low levels of chronic inflammation in their brains, similar to Alzheimer's disease conditions in older women. Then they tested the rats' ability to perform a water maze task.

Removal of the ovaries alone was not enough to decrease performance, the scientists found. But if they introduced either sustained estrogen replacement therapy or chronic brain inflammation, the animals performed more poorly on the memory task.

"We thought the estrogen [administered continuously to the rats without ovaries, similar to continuous hormone replacement therapy in human females] would be beneficial," Wenk says.

The problem, he adds, may be the continuous nature of the hormone therapy. The fact that younger rats with ovaries didn't suffer mental decline may have something to do with the ovaries being intact and the way they function normally, he says.

"Ovaries release more than estrogen," Wenk says. "It may be the cycling estrogen or something to do with the interaction with progesterone."

If there is a way to mimic more closely the hormone levels of animals with functioning ovaries that might be promising, he says.

"Long-term chronic daily therapy may be what we just need to throw out," he says.

The study "pretty much is backing up the human study," says Jon Nilsen, a research assistant professor of pharmacology and toxicology at the University of Southern California School of Pharmacy.

Echoing Wenk's suggestion, Nilsen says the new findings also lend support to the idea that fluctuating hormone levels in animals or humans with ovaries or the balance of estrogen and progesterone in younger women may be the key to finding a therapy regimen that works for older women.

Next, Wenk says, he wants to conduct research introducing variable hormone replacement therapy into animals that would mimic the levels of an animal with functioning ovaries to see if that approach might improve memory and help Alzheimer's symptoms.

Meanwhile, the take-home point for women hoping to minimize or avoid Alzheimer's disease, he says, is that hormone replacement therapy as typically given "is not beneficial for prevention, the evidence isn't there, and certainly not for treatment."

Always consult your physician for more information.