The Brain-Boosting Sex Hormone

By Sarah Richardson|Friday, April 01, 1994
RELATED TAGS: SEX & GENDER
Estrogen is more than a sex hormone. It boosts the brainpower of rats--and one day it may boost the hopes of Alzheimer’s patients.

Estrogen is the hormone that regulates a woman’s reproductive cycle--until menopause, when her ovaries begin to make much less of it. Now there is evidence that the sex hormone may also help a woman’s brain, by fostering good communication among nerve cells. A recent study of women in a California retirement community suggests that women who take estrogen supplements after menopause are less likely to contract Alzheimer’s disease, and suffer less memory loss if they do contract it.

Researchers have suspected for some time that a lack of estrogen may help explain why women appear to be at greater risk than men of contracting Alzheimer’s. Of the nearly 4 million Americans affected by the disease, three-quarters are women. In part this pattern arises simply because women live longer. But after menopause, which the average woman goes through at age 49 or 50, a woman’s estrogen level rapidly declines. In contrast, a man’s brain gets a more steady diet of estrogen throughout his life: it’s made in fatty tissue from testosterone, the male sex hormone.

In the recent California study, University of Southern California neurologist Victor Henderson and his colleague Annlia Paganini-Hill examined the medical records of 2,418 women who had died over the course of 11 years at the Leisure World retirement community in Laguna Hills. Before their death some of the women had been taking estrogen supplements for reasons unrelated to Alzheimer’s--as a treatment for osteoporosis or heart disease, for instance. Henderson found that women who had taken estrogen were 40 percent less likely to have developed Alzheimer’s than women who hadn’t. Moreover, the longer they took estrogen and the greater the dose, the more their risk was reduced. A separate study at USC showed that women who already had Alzheimer’s when they took estrogen suffered less than their counterparts who didn’t take estrogen. (The symptoms of the disease can range from simple memory loss to severe dementia.)

Since all women lose estrogen after menopause and most never get Alzheimer’s, estrogen loss is clearly not the cause of the disease. But Henderson’s study suggests it is a risk factor. There are two basic ways that estrogen may help protect against Alzheimer’s. One way would be to promote the formation of synapses--the junctions through which nerve cells communicate with one another--in the hippocampus, a region of the brain where new memories are formed. The second way estrogen may help is by preventing the degeneration of neurons that produce acetylcholine, a chemical that transmits nerve signals across synapses and that is especially important in memory. Alzheimer’s patients are known to suffer from a dearth of both synapses and acetylcholine.

As it happens, recent experiments with laboratory rats provide support for both hypotheses. In one study, Catherine Woolley of the University of Washington and Bruce McEwen of Rockefeller University found that removing the ovaries from rats causes the number of synapses in their hippocampus to decline rapidly--unless the rats are given estrogen supplements. In a second study, Meharvan Singh, James Simpkins, and their colleagues at the University of Florida showed that estrogen increases a rat’s output of an enzyme that helps make acetylcholine. The effect on the animals’ mental capacity, Singh’s group found, is significant: rats receiving estrogen, either from their own ovaries or from supplements, were twice as good as ovaryless, estrogenless rats at learning how to avoid an electric shock.

How does estrogen influence the production of acetylcholine? Singh and his colleagues measured another important difference between the two types of rats that offers a clue. In the rats without estrogen, the synthesis of a protein called nerve-growth factor declined by nearly 45 percent over a period of three months. Among other things, nerve-growth factor promotes the health of cholinergic neurons, the neurons in the brain that make and use acetylcholine. So Singh’s experiments suggest the following scenario: a drop in estrogen leads to a drop in nerve-growth factor; less nerve-growth factor means fewer cholinergic neurons; fewer cholinergic neurons means less acetylcholine in the brain; and a drop in acetylcholine reduces a rat’s ability to learn and remember important things, such as how to avoid getting shocked.

At the same time, a drop in estrogen might cause an entirely separate decline in the number of synapses in the hippocampus--the effect that Woolley and McEwen observed. I think the point is that estrogen has many effects on the brain, McEwen says, and any one of them--when estrogen is lost because of menopause--might have an impact on the way the brain works.

He and the other researchers working on estrogen express the obvious caution: rats are not humans. Yet none of them can avoid feeling excitement at the prospect that estrogen may have promise as a treatment for Alzheimer’s. Nerve-growth factor is also being considered for that role--but nerve-growth factor is a bulky protein that is too big to pass from the bloodstream into the brain. The clinical trials that are now being talked about would entail the implanting of a pump in the patient’s brain to administer the nerve-growth factor. Estrogen, says Singh, might offer a simpler alternative: it is small enough to pass into the brain, where it would encourage production of the patient’s own nerve-growth factor. And estrogen’s side effects are already well known because women are already receiving it for osteoporosis and heart disease, as well as for symptoms of menopause such as hot flashes.

Henderson thinks his own epidemiological study, together with the rat experiments, is enough to justify a large clinical trial--in effect, the human analogue of the rat experiments--to determine whether estrogen therapy can relieve the effects of Alzheimer’s. Singh agrees. Years and years ago, he says, people thought that the adult brain was pretty rigid- -that is, once a nerve cell starts to die, it’s doomed to death and there’s no hope of rescuing it. I think people are now realizing that it is not beyond the realm of possibility that degeneration of nerve cells could be arrested.
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