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Estradiol – but not Premarin – prevents neurodegeneration in women at heightened dementia risk

bottle of pillsWomen near the age of menopause and at elevated risk for dementia - owing, say, to a family history of Alzheimer’s disease, a personal history of major depression, or a genotype positive for the infamous Alzheimer’s-predisposing gene variant, ApoE4 - may want to consider talking to their doctor about estrogen-based hormone therapy.

In a brain-imaging study just published in PLOS ONE, hormone therapy protected key “early warning” brain regions from metabolic decline in women who fit that description - but only if they started therapy shortly after reaching menopause, and only if the pill they took contained just estradiol, the dominant female sex-steroid hormone. Premarin, a more widely used hormone-therapy formulation derived from the urine of pregnant mares, was far less protective.

Premarin contains more than 30 substances, with estradiol accounting for only about 17 percent. Other components exert various endocrinological effects on different tissues. In my release on the new study, I wrote:

More than 20 million women in the United States are between 45 and 55 years old - an age range at which many once were considered prime candidates for Premarin. Hormone therapy… was… widely heralded as protecting postmenopausal women from heart disease, osteoporosis and even cognitive decline.

Indeed, from 1992 through 2001 Premarin was the most widely prescribed drug in the United States. Then came the deluge. Here’s the backstory:

In July 2002, a large multicenter study of hormone therapy’s effects was abruptly halted when - contrary to expectations - woman assigned to PremPro (Premarin plus progestin, a synthetic version of progesterone, another important female steroid hormone) developed more cardiovascular disease than those getting a placebo. Within 18 months, about half of American women who’d been on hormone therapy abandoned it. Its use has since plunged considerably further.

Then in 2003, an ancillary study called WHIMS (“Women’s Health Initiative Memory Study”) reported that dementia incidence among 65- to 79-year-old women randomly assigned to PremPro was double  that of women on placebo. This disappointing finding was widely covered in the media.

But Rasgon and her colleagues’ findings are consistent with other analyses indicating that women initiating hormone therapy within five years of their last menstrual cycle experienced beneficial brain effects. In fact, major differences in trial design may explain the discrepancy between WHIMS’s decidedly negative results and the new study’s more nuanced ones.

The WHIMS women were older, on average, than those in Rasgon’s study and were beginning hormone therapy after a long hiatus during which their bodies were no longer producing substantial quantities of estrodiol. Moreover, the PremPro given to women in the active arms of WHIMS contained progestin - which, the new study shows, speeds metabolic deterioration in at least dementia-prone women’s brains.

Natalie Rasgon, MD, PhD, director of the Stanford Center for Neuroscience in Women’s Health and the study’s lead author, puts it plainly. “Hormone therapy’s neurological effect on women at risk for dementia depends critically on when they begin therapy and on whether they use estradiol or Premarin.”

Previously: Hormone therapy halts accelerated biological aging seen in women with Alzheimer's genetic risk factor, Hormone therapy soon after menopause onset may reduce Alzheimer's risk and Study shows common genetic risk factor for Alzheimer's disrupts brain function in healthy older women, but not men
Photo by Canned Muffins

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