Estrogen Therapy Gives Aging Brain Cells A Boost

In a multi-center study comparing older rhesus monkeys with younger female monkeys, researchers found that estrogen significantly improved cognitive function in older animals but not in young monkeys. The study was led by Jiandong Hao, MD, PhD, Assistant Professor of Neuroscience, and senior co-author John H. Morrison, PhD, Dean of Basic Sciences and the Graduate School of Biological Sciences, and the W.T.C. Johnson Professor of Geriatrics and Adult Development (Neurobiology of Aging). Peter Rapp, PhD, Interim Chair of the Department of Neuroscience and Associate Professor of Neuroscience, and Geriatrics and Adult Development, led the behavioral phase of the study. Partrick Hof, MD, the Irving and Dorothy Regenstreif Research Professor Neuroscience, and William Janssen, a researcher in Neurobiology of Aging, also contributed to the research.

Working with colleagues from the University of Toronto and the University of California-Davis, Drs. Morrison, Rapp, and Hao compared the outcomes of four groups of female monkeys that were ovarectomized, which induced menopause: old monkeys that received estrogen, old monkeys that did not receive estrogen, young monkeys that received estrogen, and young monkeys that did not receive estrogen. The treated animals received pure estradiol injections every 21 days while being tested on a series of cognitive tasks over the course of more than two years.

Cognitive performance tests showed the older treated animals performed almost as well as the younger animals, whereas older untreated animals displayed dramatic cognitive decline. Surprisingly, the younger animals performed equally well with or without estrogen treatments. The aged animals had their ovaries removed around the time of perimenopause--before the onset of full menopause--and began treatment within months of ovariectomy.

Microscopic studies conducted after the cognitive testing was completed revealed that in the prefrontal cortex--a region of the brain associated with cognitive tasks that Dr. Rapp used to test the monkeys--the older estrogen-treated animals showed a greater density of synaptic spines--tentacle-like structures that link brain cells to one another and aid in brain cell communication--while the older untreated animals showed no such neuronal growth. These spines are critically important for learning and memory.

The findings indicate that the debate on the potential benefits of postmenopausal hormone therapy is not yet over, says Dr. Morrison. "There's been a great deal of confusion as to whether estrogen helps or harms post-menopausal women, and our findings tell us is that there is a very critical window of opportunity in which estrogen therapy may be helpful."

Dr. Morrison notes that this critical window may be around the time of perimenopause, in which cyclical estrogen treatments as used in this study may be particularly effective in protecting the brain from age-related decline.

"We found that this increase in synaptic spines in the prefrontal cortex in the older estrogen-treated monkeys appears to have prevented age-related cognitive decline," Dr. Morrison explains. "Importantly, the increase was most pronounced among the small spines that are highly plastic and particularly important for learning and memory. Young monkeys retain a high number of these small spines even without estrogen, which explains their ability to perform well on the cognitive tasks. Estrogen levels decline in old age, so the brain may need a certain amount of circulating estrogen to remain supple. Timing may be everything."

"The increase we observed in small, thin spines suggests that estrogen allows for greater neuroplasticity, says Dr. Morrison. "Synaptic spines are lost during aging, and interestingly, it is the dynamic nature of the small-headed spines that are critical to the formation of new memories."

The younger animals retain neural plasticity in the absence of estrogen, Dr. Morrison explains, "but what's happening with the older animals is this double hit of both age and estrogen decline. These particular brain cells are not resilient enough anymore to endure this kind of double hit."

Rhesus monkeys undergo menstrual cycles and a menopause that closely mimics those of humans. Although it is well known that estrogen affects brain function, what is unclear is what form of estrogen works best, when estrogen should be given, and how much is needed to be effective. It is possible, the researchers note, that administering the same cyclical estradiol treatments to very old monkeys would result in less benefit.

"It's possible a middle-aged brain reacts differently to estrogen than a young brain, and that a very old brain might not react to estrogen at all," Dr. Morrison explains, "so this window of opportunity may be fairly narrow--we just don't know yet. If the brain is too old, then age-related decline may be difficult to reverse. However, our study suggests that if we jump before it's too late, we may possibly prevent memory loss." What is also unclear, Dr. Morrison adds, is at what point the natural course of aging trumps the effects of any estrogen treatment.

Drs. Rapp and Morrison plan to extend their research through similar behavioral and microscopic studies in monkeys that have not been ovarectomized, so that the aging process is more natural and not acutely induced.

The study will be published in the online edition of Proceedings of the National Academy of Sciences during the week of June 25.