Estrogen Paradox: Can HRT Be Both Good and Bad for the Brain?

While estrogen is important to cognition, HRT sometimes shrinks older women's brains.

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By Bernadine Healy, M.D.

Estrogen is living up to its long-held reputation as the memory molecule. It gets soaked up by the brain and promotes nerve connections in all manner of species—from man to ape, rodent to songbird. But, paradoxically, it is also a molecule that can shrink an older women's brain, accelerating its demise into the dark night of Alzheimer's disease. In research from the Women's Health Initiative released this week, brain scans helped explain why some women show deterioration when given hormone replacement therapy (HRT) begun in their older years.

The two new MRI studies from the NIH and Wake Forest University found, surprisingly, that the primary problem is neurodegenerative—that is, the destruction of neurons—not indirect damage caused by ministrokes, as researchers had anticipated. They identified a small amount of brain shrinkage and loss of working tissue in the brain's memory center and in higher brain regions typical of what's seen in Alzheimer's.

What might be too easily overlooked, however, is that the brain shrinkage and acceleration of the development of Alzheimer's was not present in all older women taking the hormones: Specifically, those women who did not have signs of impaired reasoning or thinking when first starting hormones did not show shrinkage or mental deterioration. That is, estrogen was trouble mainly to brains already going downhill.

Neuroscientists are actually rather excited by these findings, which just might reconcile some seemingly contradictory observations that have given estrogen its checkered reputation. On one hand, estrogen aids neurons. Brain cells treated with the hormone in the lab, for example, suddenly blossom, sprouting new connections, wiring new networks, and doing the kind of work that allows creation of memories and enables complex thinking. Withdraw estrogen, and the cells start to wilt. And if scientists give a brain cell a drink of estrogen and then hit it with a deadly toxin, the neuron is more resilient than it would be without the estrogen pretreatment.

On the other hand, some neuroscientists note, estrogen can be a slayer of brain cells if the neurons it encounters are weak or injured. As if pruning the sick to protect the well, the hormone seems to ignore the weak cells, or even push them to self-destruct. In scientific lingo, estrogen has a "healthy cell bias."

Clearly, it's an oversimplification to call estrogen all good or all bad or to say that it's for every woman or for no woman, or for every neuron or for none. What researchers are doing today is making sense of the competing findings that have have made estrogen, at turns, an angel or a devil for years.

Unraveling the estrogen-brain paradox is one of the more important outcomes of the Women's Health Initiative. The WHI's surprising initial results in 2004 overturned the embedded notion that hormone replacement therapy was life-saving preventive medicine for virtually all post-menopausal women. That finding broke the widespread practice of recommending a lifetime of HRT almost by reflex. In particular, it stopped cold the practice of starting women in their 60s, 70s, and 80s on hormones, women who for the most part had already weathered menopause years before without a whiff of pills or patches. Imagine how much women's brain tissue has been spared since then by changing this well intentioned but wrong preventive health practice.

A better understanding of HRT's effects in patients and in the lab has shown that there may well be a critical window of opportunity for some post-menopausal women's brains to benefit from a protective estrogen. And, at the least, that means starting replacement therapy at the time of menopause. But doctors, in all humility, don't yet have the answers as to just what formulation, for how long, and in which patients an estrogen boost would predictably help keep brains well.

Disclosure: As NIH director in 1991, Dr. Healy began the Women's Health Initiative.