" Hormones connect in intriguing ways to diseases where the immune system attacks the body, such as arthritis or MS. Women are two to three times more likely than men to get those diseases, and roughly nine times more likely to get lupus, another autoimmune disease, Offner said.

But if high estrogen levels protect pregnant women, why do more women get MS to start with? Offner thinks the reproductive cycles of high and low estrogen levels are the culprit. She thinks the disease could be treated with steady delivery of estrogen -- better yet, with a SERM (targeted estrogen that does not cause breast or uterine growth) that men and women both could use safely. "

Full Article Text A hormone's handiwork

Researchers delve into discoveries of estrogen's effects on the body beyond reproductive purposes

01/21/04

ANDY DWORKIN

Scientists are studying a drug that may protect against brain damage, influence weight and appetite, fend off Alzheimer's disease, battle multiple sclerosis, affect mood and slow the ravages of aging.

It's called estrogen.

Every doctor and fifth-grade sex-ed pupil has long known that estrogen helps drive sexual changes in women, such as preparing the uterus and milk ducts for childbirth.

But since the 1990s, scientists have uncovered a host of other, often surprising, roles for the estrogens, a family of closely related hormones. In men and women, estrogens have been found spurring powerful changes in bones, blood vessels, the liver and the brain. That widespread influence grew notorious last year, when a study of hormone-replacement therapy showed increased risk for breast and uterine cancer, heart disease and stroke.

The news spurred a scientific quest to figure out exactly how, on the level of genes and proteins, estrogen affects so many body functions. The final goal of that knowledge: creating drugs that mimic estrogen's good effects, such as aiding brain processes, without promoting diseases.

Oregon Health & Science University researchers unveiled one such drug this fall, which may reveal an entirely new way that estrogen works on the brain. Early tests indicate that the chemical, called STX, could help menopausal women control hot flashes, and maintain normal mood and sleep patterns, without any effect on the reproductive system.

"This drug has the potential to change the way we treat postmenopausal women," said Dr. Peter Kohler, OHSU president.

A host of other estrogen studies at OHSU join the STX work, making this "a crucial time" for the Portland university's research into the hormone, said Dan Dorsa, OHSU vice president for research. Dorsa, himself a hormone researcher, said OHSU has "a long history" of studying hormones and neuroscience, enhanced by the recent hiring of several Johns Hopkins University anesthesiologists who study estrogen's effects on brain cells.

"We're trying to make it (estrogen) a bigger deal than it has been in the past," said Richard Traystman, one of the Hopkins researchers and OHSU's associate vice president for research.

Nature's stroke drug? The Hopkins crew is pursuing estrogen's intriguing ability to protect brain cells starved of oxygen, such as after a stroke or cardiac arrest.

That has been a controversial topic since July, when the National Institutes of Health stopped its study of PremPro, a hormone replacement drug. Women taking PremPro in that study had slightly more strokes than other women, implicating one of the drug's two hormones: estrogen or progesterone. And other studies show that estrogen may increase blood clotting, which could cause strokes by blocking vessels to the brain.

Despite those studies, a host of evidence shows that estrogen helps brain cells to protect themselves from damage when oxygen runs short, such as after a stroke, said Patricia Hurn, one of OHSU's new anesthesia researchers. Hurn has done extensive studies in rodents, indicating that higher levels of estrogen before a stroke lead to less brain damage afterward. Other research on cell cultures and animals supports the idea, she said.

Hurn noted that, although women on PremPro had slightly more strokes, they did not die from strokes any more often. So the drug may have lessened the severity of strokes, even if it helped cause them.

"Whether or not estrogen prevents stroke, it reduces death from stroke," she said.

Hurn also noted that women have strokes much less often than men, until they hit menopause; then they catch up. She suspects estrogen levels.

Traystman noted similar trends in people whose hearts stop beating. Doctors know it is often harder to revive men after cardiac arrest than women, he said, a pattern that holds in the rodents he studies.

"If you take male and female mice and give them a cardiac arrest and CPR, the female mice always do better," emerging with less brain damage, Traystman said. But he said female mice with low estrogen levels -- older mice or those who had their ovaries removed -- react "pretty much like the male" mice.

"We've also done experiments where you can inject estrogen just at the time you start resuscitation and, lo and behold, they do better," Traystman said.

Traystman and Hurn said there have been no large human trials yet giving estrogen to protect against stroke. But a few smaller trials have shown that "estrogen doesn't do a thing" in humans with stroke, Traystman said. "It's caused a major uproar in the community. It's become a very hot topic."

The lack of effect could stem from estrogen's tendency to increase clotting. Or it could be because of the studies' design; for instance, estrogen was given too late to benefit people.

Hurn expects more studies on whether estrogen, or related drugs, can protect oxygen-starved brain cells. The hormone is an attractive stroke treatment because "it works on a lot of mechanisms" in the brain, she noted.

For instance, estrogen neutralizes oxygen "radicals," charged particles that can kill nerve cells. The hormone also may help dilate blood vessels, enabling more blood to get to the brain when the heart restarts. And it seems to spur genes to make proteins that limit cell death. Engineering estrogen If estrogen is ever going to be a drug for stroke, or many other diseases, scientists will need to root the devil out of the details.

At OHSU, Dorsa and others are laboring to outline which molecules in the body estrogen interacts with to create various changes. Scientists have found two distinct molecules -- estrogen receptors alpha and beta -- that interact with estrogen in different ways.

Dorsa, who studies how hormones change cultures of brain cells, said estrogen first was known to act directly on DNA. The hormone would hit a receptor in the cell's nucleus, causing the cell to make more copies of certain genes. That's how estrogen causes cell growth in the breast and uterus during menstrual cycles.

But the brain doesn't grow and swell like the uterus, so scientists looked at estrogen's action outside the nucleus. Dorsa and others have found that estrogen can also link to receptors at the cell's surface, similar to the way growth hormones work. In this system, estrogen causes chemical changes that let proteins do work in the body without directly affecting DNA.

The dream of academic and drug company scientists is to catalog the shape, chemical makeup and location of estrogen receptors throughout the body -- as well as what changes happen when these molecules get turned on or off. That could generate more designer chemicals with the ability to affect select receptors. In theory, such chemicals -- called selective estrogen receptor modulators, or SERMs -- could protect against Alzheimer's or block hot flashes without causing changes to the reproductive organs, Dorsa said.

Drug companies already sell two SERMs. The first, tamoxifen, blocks the effects of estrogen in the breast and is used to treat breast cancer. But tamoxifen acts like estrogen on the uterus, increasing cancer risk, and doesn't have estrogen's positive effects on the brain.

The second SERM, raloxifene, acts like estrogen to strengthen bones and fight osteoporosis. It does not spur uterine or breast cells to grow, and might even protect against cancer at those sites (the government is funding a study of that now). But researchers have not reported strong effects of raloxifene on brain functions, such as hot flashes.

The search for better brain SERM led researchers at OHSU and the University of California at San Francisco to STX.

The scientists sought out chemicals that were similar to estrogen but did not interact with the two known estrogen receptors, said Martin Kelly, an OHSU researcher. They assumed that, by avoiding those two receptors, they could avoid cancer risks, Kelly said.

That made STX's effects on the brain hugely important, Kelly said, because it indicates the drug is flipping a previously unknown switch at the surface of cells. Estrogen itself worked through the same chemical pathway, showing that a third estrogen receptor may be in the body.

"It's proof of principle that there's another class of receptors out there," he said.

That finding generated "huge interest" from academics and drug company researchers at a New Orleans conference, Kelly said. So did tests showing that STX affects a set of brain cells that control a number of functions, including stress, hunger and temperature regulation (think hot flashes).

OHSU scientists are studying how STX affects rodents. And other scientists are chasing different SERMs.

"Almost every pharmaceutical company, and a lot of people in academia, are trying to find a way to get the effects of estrogen in the brain without the systemic effects," said Cynthia Bethea, a researcher at the Oregon National Primate Research Center - Hillsboro.

Bethea proved that the cells in primate brains that make serotonin, the chemical influenced by popular antidepressant drugs, contain estrogen receptor beta. Estrogen acts "quite dramatically" on those cells, she said, further spurring the search for SERMs that might influence depression, memory and other mental functions without adverse side effects.

Another primate center researcher, Judy Cameron, recently published a study indicating that falling levels of estrogen might act to increase hunger and weight.

An MS treatment? Back on Marquam Hill, Dr. Halina Offner is studying another, striking idea -- that estrogen can help regulate the immune system, limiting the harm from multiple sclerosis. That disease happens when the body attacks the lining of nerves in the spinal cord.

Hormones connect in intriguing ways to diseases where the immune system attacks the body, such as arthritis or MS. Women are two to three times more likely than men to get those diseases, and roughly nine times more likely to get lupus, another autoimmune disease, Offner said.

Another link: "Sex hormones are increased during pregnancy. And very often, women with MS enter remission during pregnancy," she said, then relapse after childbirth.

But if high estrogen levels protect pregnant women, why do more women get MS to start with? Offner thinks the reproductive cycles of high and low estrogen levels are the culprit. She thinks the disease could be treated with steady delivery of estrogen -- better yet, with a SERM that men and women both could use safely.

Offner successfully has used estrogen and related compounds to treat EAE, a mouse version of MS. She said the benefit showed up both when she gave an estrogen before the mouse got sick and when she gave it only after the EAE set in.

Tracking that effect, Offner found evidence that estrogen keeps the white blood cells that inflame nerves from entering the brain and spinal cord. She is studying whether estrogen increases the number of another kind of blood cell, which keeps the inflammatory cells in check.

Offner said estrogen also eased illness in a mouse model of arthritis she made. She is continuing to test different SERMs on mice with EAE. And she thinks OHSU scientists will start testing a SERM on people with MS as soon as this year.

"I think there's hope here," she said. "It's amazing. I think these hormones are amazing."

Andy Dworkin: 503-221-8239; andydworkin@news.oregonian.com