Study
finds estrogen therapy gives aging brain cells a
boost
Cyclical, long-term estrogen injections protected brain cells
from age-related deterioration, according to a
new study conducted at Mount Sinai School of
Medicine. The study suggests that age is a
factor in estrogen treatment and sheds light on
the intricate relationship between mind, age,
and hormones. The study will be published in the
online edition of Proceedings of the National
Academy of Sciences during the week of June 25.
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.
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About The Mount Sinai Medical Center
The Mount Sinai Medical Center encompasses The Mount Sinai
Hospital and Mount Sinai School of Medicine. The
Mount Sinai Hospital is one of the nation’s
oldest, largest and most-respected voluntary
hospitals. Founded in 1852, Mount Sinai today is
a 1,171-bed tertiary-care teaching facility that
is internationally acclaimed for excellence in
clinical care. Last year, nearly 50,000 people
were treated at Mount Sinai as inpatients, and
there were nearly 450,000 outpatient visits to
the Medical Center. Mount Sinai School of
Medicine is internationally recognized as a
leader in groundbreaking clinical and
basic-science research, as well as innovative
approach to medical education. With a faculty of
more than 3,400 in 38 clinical and basic science
departments and centers, Mount Sinai ranks among
the top 20 medical schools in receipt of
National Institute of Health (NIH) grants.
