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.