Perplexing Estrogen Findings Drive Research

by Brenda Patoine

November, 2006

There is hope for hormone therapy in women, but it won’t be your mother’s regimen.

That was one theme that emerged from a series of SfN reports on estrogen and the aging female brain, an area of research that is still reeling from the Women’s Health Initiative–Memory Study three years ago. The findings—no cognitive benefit and a higher risk of dementia for older women taking a popular combination estrogen-progesterone formula (Prempro)—came as a surprise and left women wondering what to do.

A special symposium at the meeting and a concurrent review in the Journal of Neuroscience hint at answers to central questions the study raised: Why did earlier, promising results in the lab not translate to humans? How real are the brain benefits of estrogen, and why did they not show up in the study? What does the future hold for hormone therapy?

Age Matters

One of the primary messages is the importance of age when considering estrogen’s effects on the brain, said John Morrison, a neurobiologist at Mount Sinai School of Medicine in New York who chaired the symposium and was lead author on the Journal of Neuroscience article.

In the Women’s Health Initiative study, subjects’ relative age, both at the time of enrollment and at the time treatment started, were important in whether hormone therapy produced a negative outcome. Older women who initiated hormone therapy later in life were less likely to get any cognitive benefit and more likely to have an increased risk for cognitive problems.

“Timing is everything,” said Andrea Gore, a neuroendocrinologist at the University of Texas at Austin. “The aged brain reacts differently to estrogen than does the brain of young women.”

Gore studies age-related changes in the “reproductive axis,” a brain circuit that links the hypothalamus, pituitary, and ovaries. Recent work by her group and others suggests that with age, this circuit changes and becomes less responsive to estrogen.

At the cellular level, the number and distribution of estrogen receptors fluctuates throughout life and their relative distribution across the body and brain changes. These receptors are the gates through which estrogen influences cellular and genetic activity, so having more or fewer of them at various times is significant.

A Healthy Bias?

Another possible explanation for the Women’s Health Initiative findings, suggests molecular pharmacologist Roberta Brinton of the University of Southern California, is that estrogen has a “bias” to benefit only healthy cells. She thinks the women in the study who developed dementia already may have had some degree of undiagnosed damage before they began hormone therapy, and the hormones exacerbated it.

“When a healthy nerve cell is exposed to estrogen in a culture dish, it takes on a proactive defense state and has a 25 to 50 percent better chance of surviving than a cell not exposed to estrogen,” Brinton said. “But, if the cell is already degenerating, estrogen increases its demise. This suggests that we have to treat cells while they’re still healthy.”

Brinton’s team made these discoveries by creating a series of experiments in which estrogen was applied either to healthy nerve cells or to degenerating cells. She is now expanding this research by studying the effects of hormone therapy in a mouse model of the human menopausal transition.

Her goal is to develop laboratory systems that have the greatest applicability to women, thereby avoiding the translational disconnection between previous research on estrogen and the results of the Women’s Health Initiative–Memory Study.

Brinton’s laboratory and others have mapped out in painstaking detail the multistep signaling pathways triggered inside cells when estrogen locks on to one of its receptors. It is a complicated picture, made more so by the fact that estrogen acts through at least two receptors (called alpha and beta subtypes) that are distributed at two cell locations (nucleus and membrane).  

The hormone’s effects are different depending on the receptor type, its location in the cell, and the cell’s location in the body (e.g., brain vs. breast). By understanding how these effects differ, it should be possible to design molecules that selectively initiate beneficial actions while avoiding harmful effects.

In brain cells important for memory processes, Brinton said, estrogen’s actions converge on the mitochondria, tiny units, called organelles, inside the cell nucleus that produce the energy for cellular activities. Mitochondrial dysfunction is thought to be a possible common mechanism underlying many neurodegenerative diseases, so keeping mitochondria in top shape is an attractive therapeutic strategy.

“Estrogen induces a fairly large increase in mitochondrial energy production and improves cell survival, presumably through mitochondrial-based mechanisms,” Brinton said. She believes this may be the key to estrogen’s reported neuroprotective qualities and possibly to the beneficial effects on memory that earlier studies found.

The Future of Hormone Therapy

Armed with these new understandings, Brinton’s group and other researchers are focusing on designing pharmacologic compounds that promote specific, clinically useful actions such as neuroprotection or neuronal survival while avoiding negative effects, all by targeting certain receptors over others.

This is the strategy behind two current drugs called selective estrogen receptor modulators, or SERMs, that are used to suppress cancer of the breast. The drugs, tamoxifen and raloxifene, act selectively to block estrogen receptors in the breast that drive tumor growth. Neither has a significant effect in the brain, however.

The next generation of SERMs will be even more targeted as the science of estrogen’s actions advances. For example, Brinton’s lab is now developing a “neuroSERM” that preferentially activates protective estrogen mechanisms in the brain while inactivating receptors in the breast or uterus.