Two very different recent papers come to a similar conclusion: cyclical, physiologic hormone replacement therapy (HRT) may aid memory in postmenopausal women.

One paper found native progesterone, as it is in its natural state cycling the body, helps memory early post-menopause. The other paper found cyclic, physiologic, administered estrogen helps memory after induced menopause.

“Together these results point toward the importance of maintaining hypothalamic-pituitary-gonadal (reproductive system) hormone balance for optimal cognitive performance,” says Wisconsin Alzheimer’s Institute Research Director Craig Atwood, uninvolved in the studies.

That is, early in menopause, some women worried about cognition may want to try preserving natural cycles of reproductive hormones including estradiol (estrogen), progesterone, testosterone, and lutenizing hormone. But they may want do to it physiologically, this time.

For decades, millions post-menopausally took Prempro, a drug now owned by Pfizer. Most stopped in 2002, when the National Institutes of Health (NIH) halted a large Women’s Health Initiative (WHI) trial finding Prempro hiked some diseases like breast cancer and heart disease. Medical associations advised women to only take HRT if symptoms like hot flashes were severe.

But many scientists grumbled Prempro is not physiologic (identical to human hormones). Its progesterone is a different shape, letting it cling too tightly to some cell receptors. Its estrogen is shaped like human estrogen, but comes from mare urine and has some different qualities. Prempro hormones were also not taken physiologically, but in a single pill daily, undergoing a liver first-pass. Naturally, hormones cycle differently, and make no liver first-pass.

And the average WHI woman was in her 60’s, when many cells down-regulate hormone receptors after years of unuse. It may be key to start HRT during an early post-menopause “window," some top researchers said.

“The WHI was conducted to examine a very specific drug,” said Columbia University neuroscientist Dominique Toran-Allerand after the WHI shut-down. Toran- Allerand studied estrogen and the brain. “Now we know: Prempro doesn't have effects many wanted. But many have been globally transferring this to mean all HRT’s. It makes no sense.”

Slowly, studies of more physiologic hormones—estradiol and micronized progesterone—have emerged. Among the most notable are KEEPS and ELITE, sponsored by the Kronos Longevity Research Institute and schools including Yale and Columbia.

Not enough time has elapsed for conclusions. But two recent studies in Proceedings of the National Academy of Science (PNAS) are promising, experts say.

One looked at data from post-menopausal ELITE women pre-HRT. Led by Wendy Mack of the University of Southern California, the study examined 643 post-menopausal women. It found native progesterone in the blood is “significantly positively correlated with verbal memory and global cognition in early (menopausal) women,” the authors wrote. The study also found a positive correlation between sex hormone binding globulin and verbal memory.

The Mack team did not find native estradiol blood levels mattered to cognition. Atwood says there may be a reason. “This study finds an important association between circulating progesterone, and cognitive performance, early post-menopause. Since estradiol up-regulates progesterone receptor expression, it is interesting to speculate effects of progesterone in promoting early post-menopause cognitive performance are due to 'residual' progesterone receptor expression closer to menopause.”

Atwood says the study supports the idea that beneficial effects of physiologic HRT “immediately post-menopause, in the 'critical window', are due to suppression of circulating gonadotropins (like lutenizing hormone). Unlike circulating estradiol, which remains at a low level throughout post-menopause, circulating gonadotropins are dramatically elevated immediately post-menopause, then slowly decline to lower levels. HRT blunts this dramatic increase in gonadotropins during the critical window, limiting neurodegeneration and cognitive decline.”

John H. MorrisonThe second recent PNAS study, led by John Morrison of the Mount Sinai Icahn School of Medicine, found removal of monkey ovaries impaired memory, and altered mitochondria (power packs) in neural synapses. This was reversed by cyclic, physiologic estradiol.

“The fact our treatment is cyclical is very important,” says Morrison, Dean of the Graduate School of Biomedical Sciences. “ Other papers of ours have shown chronic estradiol, or estradiol plus progesterone, treatments do not enhance cognition and do not enhance synaptic parameters.”

The reason, he thinks: brain estrogen receptors are “down-regulated” when bombarded with hormones non-stop, non-physiologically.

Says Atwood: “The elevation in (altered) mitochondria seen in ovariectomized monkeys, but not in natural menopause, suggests production of a factor by the ovary post-menopause preventing mitochondrial alterations. Measuring circulating estradiol concentrations in post-menopausal and ovariectomized monkeys would ascertain if the ovary-intact monkeys produce low levels of estradiol that offset these changes, or if another factor produced by ovaries prompts mitochondrial changes.”

But, he says, as cyclic estradiol in aged ovariectomized monkeys reverses mitochondrial alteration, and as it is unlikely post-menopausal ovaries produce much estradiol, the “reversal is likely due to suppression of circulating gonadotropins by cyclic estradiol administration. Gonadotropin levels are more elevated with ovariectomy than menopause. It would depend on how far post-menopause these monkeys were, since gonadotropins decrease the further from menopause you go. Or cyclic estradiol might increase progesterone receptor expression, and the reversal of mitochondrial (alteration), promoting cognitive performance.”

Either way, the papers hint “cyclic physiological administration of estradiol and progesterone is beneficial.”