Estrogen and the aging brain

As women advance in age, pregnancy and childbirth become increasingly dangerous and destructive. Perhaps to protect us, we women have evolved to be infertile later in life: our ovaries stop producing estrogen, causing our reproductive systems to gradually cease operations. Thus rendered barren, we can devote our maternal resources to mentoring and supporting our children and grandchildren. The rosy "grandmother hypothesis" is, however, not the only theory for the evolutionary origin of menopause.

The cessation of estrogen production also results in a number of debilitating symptoms, such as hot flashes, loss of short-term memory, and declining abilities to concentrate and learn new tasks, which would have put older women at greater risk for predation. Accordingly, some have hypothesized that menopause evolved as a way to "thin the herd," eliminating non-reproductive members of society and leaving food and other resources for the young. (Love you, Gumma!)

[This "culling agent" theory receives little support; the predominant theory as to why cognitive abilities decline is that conditions manifesting later in life (especially after reproductive age) are simply not subjected to the pressures of natural selection.]

Regardless of prehistorical reality, humans have evolved the propensity to thwart nature, creating the pharmaceutical industry and one of its many gifts: hormone replacement therapy (HRT). HRT does not rescue infertility, but is intended to mitigate the other lamentable effects of menopause, such as those impacting cognitive function.

The aging brain, while not suffering from notable cell death (except in conditions like Alzheimer's and Parkinson's Disease), is afflicted by significant changes in the connections (synapses) between neurons, within otherwise intact neural circuits. Certain molecules with essential roles in synaptic communication (e.g. glutamate receptors) change in quantity and location. These molecular changes are accompanied by significant structural alterations to the synapses themselves. Two regions display the greatest vulnerability to these changes: the prefrontal cortex (PFC), involved in attention and working memory, and the hippocampus, involved in many types of memory formation. Although these changes are inevitable concomitants of brain aging, they are exacerbated by the drop in estrogen levels experienced by women undergoing menopause, particularly in the PFC.

Estrogen, like all hormones, acts by traveling through the membrane of a cell to the nucleus, where it switches certain genes on or off, thereby regulating protein production. Of the many genes under the direct control of estrogen are the NMDA receptor (a key molecule for synaptic communication, in particular synaptic plasticity), elements of the cholinergic system (involved in attention and working memory), and genes that influence neuronal survival and structure. In particular, estrogen is known to enhance the number and strength of connections in the PFC of female rhesus monkeys which have had their ovaries removed ("ovariectomized," or OVX). The relevance to the human menopausal situation, however, involving both age and estrogen loss, was heretofore unknown.

A new study by John Morrison at Mt. Sinai School of Medicine investigated this issue by OVXing old and young rhesus monkeys, and treating half of each group with estrogen. The group then tested the monkeys on a task of short-term memory (STM), a component of working memory, in which the monkeys had to remember the location of an object after an increasing delay. They found that aged OVX monkeys which had not received estrogen treatment performed significantly worse than any of the other three groups (aged OVX + estrogen (E), young OVX + E, young OVX), indicative of significant cognitive decline. Moreover, the two groups of young animals performed equivalently, regardless of whether they received estrogen treatment, and the aged OVX + E group performed equally well as the former two. This surprising finding indicates that the estrogen treatment in the aged monkeys was sufficient to improve their cognitive function to levels comparable to their younger peers.

After cognitive testing, the researchers analyzed the brains of all monkeys, discovering that, in the PFC, estrogen increased synaptic density in both young and old OVX monkeys. Highest synaptic density was observed in young OVX + E monkeys, followed by comparable levels between young OVX and aged OVX + E, and lowest density in aged OVX without E. Moreover, estrogen treatment resulted in a significant increase in a particular subpopulation of synapses, which exhibit high dynamism and plasticity.

These findings indicate a complex interplay between estrogen and age, by which "young monkeys without [estrogen] can sustain excellent cognitive function against a background of dynamic spine plasticity." The one-two punch of age and estrogen loss, however, may be sufficiently destructive to impair an animal's cognitive function. By promoting the growth of new, dynamic synapses, estrogen may partially compensate for the effects of aging.

The implication with respect to HRT is that the timing of treatment is crucial. It may be important to begin treatment when ovarian hormone levels just begin to fall, at perimenopause, while synaptic plasticity mechanisms are still robust and resilient. Thus, this study contributes to the enormous body of HRT research (which currently consists of heaps of conflicting information). It has been suggested that the timing of hormonal intervention may underlie many of these contradictory data, and this study may lend some credence to this hypothesis and clear these cloudy waters.

Reference: Hao J et al. Interactive effects of age and estrogen on cognition and pyramidal neurosn in monkey prefrontal cortex. PNAS 2007 Jun 25 [Epub ahead of print].