And the brain, scientists have learned in recent decades, is loaded with these receptors. Knowing this makes it easier to understand how perimenopause could start inside aging ovaries and set off such a wild cascade of effects. If you’re a typical woman moving through your 40s or 50s, your lifetime egg supply is running out; as that happens, the intricate, multihormone reproductive-signaling loop grows confounded, its triggers altered by the biology of change. The brain and ovaries, the primary stops along this loop, start misreading each other’s demands for action. This can make estrogen production crank up frantically, crash and then crank up again. Something also goes awry with most women’s thermoregulatory systems, producing hot flashes in around three-quarters of us — nobody yet knows why, exactly, nor why certain women go on flashing for many years while some escape the whole must-remove-outer-garments-now phenomenon entirely. There’s an admirably clear explanation of the complete process in a recent book called “Hot Flashes, Hormones and Your Health,” by JoAnn Manson, a Harvard medical professor who worked with both W.H.I. and Keeps. My favorite illustration in Manson’s book shows an actual woman’s hormone fluctuations as measured before, during and after peri­menopause; the “before” graph is a row of calm, evenly spaced ups and downs, various hormones rising and falling in counterpoint and on cue. The lines in the “after” graph are virtually flat. The “during” graph looks as if somebody dynamited a mountain range.

Not all women, Manson notes, experience disruptions as robust as this unidentified patient’s. But consider the mess of internal rearrangement we’re looking at: the body’s overall estrogen production is waning as the ovaries start atrophying into full retirement; and here simultaneously, at least for some of us, is this great Upheaval of During. The combination of the two can be — how could it not, I thought, the first time I studied the three graphs — a hellacious strain on the brain. Tracing the exact mechanics is still a work in progress, but they surely include some disruption of signaling to the neurotransmitters that make us remember things, experience emotions and generally choreograph the whole thinking operation of the human self.

“There are all these fundamental cognitive functions that many perimenopausal women complain about, and one of those fundamentals is attention,” Roberta Brinton, the U.S.C. scientist, told me. “When you can’t hold your attention to a thought. Where you’re in constant start mode, and you never reach the finish mode. That is devastating.”

This was Brinton, as it happens, describing herself. It’s why she first went on estrogen (estradiol, accompanied by natural progesterone) when her own perimenopause kicked in a few years ago. We were sitting in a campus garage in her Prius one day, and I asked her what made her so sure her own midlife difficulties — she had the hot flashes, which were obvious, but also the sleep disruption and the infuriating distractibility — were the product of hormonal events, not some womanly existential crisis. We get a lot of that, societally. It’s meant to be empathetic. Your role in life is changing, Mrs. Brain Seized by Aliens! Your children are growing up, you’re buying expensive wrinkle cream, ice cream makes you gain weight now, of course you’re distraught! “Because with estrogen — ” Brinton looked at me sharply, and then smiled — “I don’t have attention-deficit disorder.”

We walked back up to her laboratories, which are spread along a many-roomed warren full of cell incubators, centrifuges and computers. Brinton has thick black hair and a demeanor of lively, good-humored authority; it’s easy to envision her as the passionate science professor in crowded lecture halls. But in her labs the work is all rats and mice, many of them surgically or genetically altered to serve as surrogates for adult humans in various stages of maturation or disease. Removing the ovaries from female rats, for example, sends them into low-estrogen mode. Mice can be ordered bred with Alzheimer’s. The plaque that clogs the brains of Alzheimer’s sufferers, a noxious memory-disrupting substance called beta amyloid, is available as a chemical distillate, which means Brinton’s team can experiment with that too — beta amyloid dropped into the brain cells of healthy low-estrogen rodents; or estrogen dropped into cells already damaged by beta amyloid.

That’s why Brinton says that the timing hypothesis — the proposition that estrogen could bring great benefit to a woman who starts it in her 50s while having the reverse effect on a woman 10 years older — makes sense even though it is still experimental. She and other scientists know there are ways estrogen improves and protects the brain when it is added to healthy tissue. It makes new cells grow. It increases what’s called “plasticity,” the brain’s ability to change and respond to stimulation. It builds up the density and number of dendritic spines, the barbs that stick out along the long tails of brain cells, like thorns on a blackberry stem, and hook up with other neurons to transmit information back and forth. (The thinning of those spines is a classic sign of Alzheimer’s.)

But when estrogen hits cells that are already sick — because they’re dying off as part of the natural aging process or because they’ve been damaged by beta amyloid — something else seems to happen. Dropped in as a new agent, like the wrong kind of chemical solvent sloshed onto rusting metal, estrogen doesn’t strengthen or repair. It appears useless. Sometimes it sets off discernible harm. You may recall additional W.H.I. news a few years ago about hormones increasing the risk for aging-related dementia; those stories emerged from a subgroup of W.H.I. participants who were all at least 65 when they started the hormones. There are arguments about that data, like nearly everything else connected to the W.H.I., but the age factor alone reinforces what Brinton and other timing-hypothesis researchers observe in the labs when they give estrogen to ailing cells. “It’s like the estrogen is egging on the negative now, rather than the positive,” she said. “We know that if you give neurons estrogen, and then expose them to beta amyloid, many more will survive. But when we expose them to amyloid and then give them estrogen — now you don’t have survival of the neurons. In some instances, you can actually exacerbate their death.”