Estrogen’s Benefit Tied to Age: Good for the Young, Bad for the Old

Series - Alzheimer's Association International Conference 2018:

Part 2 of 2. Click here for Part 1. 

The story of estrogen and Alzheimer’s disease is one of controversy. Epidemiological studies consistently suggest the hormone protects the brain, but the landmark Women’s Health Initiative Memory Study (WHIMS) found that hormone replacement therapy harmed cognition in older women who were long past menopause. The data led to the hypothesis that the effect of estrogen depends on age, with younger women benefiting the most. At the Alzheimer’s Association International Conference, held July 22–26 in Chicago, speakers presented the latest data in support of this idea, reporting that hormone replacement therapy given soon after menopause neither helps nor harms the brain. Meanwhile, new epidemiological data presented in Chicago reinforced the notion that a higher lifetime exposure to estrogen preserves cognition, with early menopause significantly boosting dementia risk. These studies still leave unclear how best to protect a woman’s brain from decline. One hint came from a small study that correlated first trimesters of pregnancy with a lower risk of dementia later in life. Because first trimesters exert lasting immunosuppressive effects on women’s bodies, the data suggest that immune regulation could help protect the female brain.

Fifteen years ago, the massive WHIMS study shocked researchers, who had been riding a wave of estrogen’s supposed health benefits, with its finding that oral conjugated equine estrogen (CEE) doubled the risk of dementia, contrary to prevailing data from smaller studies (May 2003 news). However, the women in that study were 65 or older. Researchers were quick to point out that observational data showing a benefit to cognition came from younger women, near the age of menopause (Mar 2006 webinar; Nov 2011 news). 

Since then, follow-up studies have borne out this timing hypothesis. Younger women enrolled in the Women’s Health Initiative, who had started hormone therapy between the ages of 50 and 54, had no cognitive deficit compared to those on placebo (Jun 2013 news). Among the older WHIMS participants, women with diabetes suffered the greatest loss of brain volume, suggesting that metabolic health affects whatever estrogen does to the aging brain (Sep 2015 news; Espeland et al., 2015). 

In Chicago, Carey Gleason of the University of Wisconsin, Madison, reported the latest data from subsequent trials of hormone replacement therapy. She co-leads the Kronos Early Estrogen Prevention Study (KEEPS), which compared three formulations of hormone replacement therapy administered within three years of menopause to a cohort of 662 women. The therapies were oral CEE, an estradiol patch, or cyclic progestin. After four years, none of these therapies changed any measure of cognition relative to placebo, Gleason reported. However, oral CEE did improve mood, lowering the incidence of anxiety and depression (Gleason et al., 2015). Menopausal women have an increased risk of depression (Bromberger et al., 2011). 

Similar findings came out of the Early versus Late Intervention Trial with Estradiol, Gleason reported. ELITE compared women who started oral estradiol within six years of menopause to women who started more than 10 years after. After five years on drug, neither group had any cognitive deficits compared to placebo. Those who started treatment early, however, did have less atherosclerosis than the placebo group, suggesting a benefit to heart health (Hodis et al., 2016). 

Gleason emphasized that all the participants in these two studies were in good health, with normal metabolic markers and no chronic conditions. For these relatively young, healthy women, short-term hormone therapy has no effect on cognition, Gleason concluded. At the same time, she hinted that estrogen could have distinct effects on subgroups of women. In a small substudy, Gleason found the amyloid burden on PiB PET to be lower in 21 KEEPS participants who used the estradiol patch than in 30 women on placebo. The difference seemed to be driven by ApoE4; the 10 carriers using the patch accumulated less amyloid than the five on placebo (Kantarci et al., 2016). An ongoing KEEPS continuation study will follow up with participants 12 years after they started therapy to check for long-term effects, and will examine amyloid burden in a larger sample.

While estrogen’s benefit for old brains is in doubt, the hormone’s importance for younger women seems unquestioned. In Chicago, Paola Gilsanz of the University of California, San Francisco, strengthened the case that lifetime exposure to estrogen lowers AD risk. She analyzed data from 14,595 women between the ages of 40 and 55 who were seen in Kaiser Permanente clinics in California between 1964 and 1973. The cohort was diverse, with 68 percent white, 16 percent African-American, 6 percent Asian, and 5 percent Latina in the mix. The women had an average of three children and one miscarriage each, and an average reproductive period of 34 years. The average age of menarche was 13, and menopause, 47. The researchers assessed for dementia by examining medical diagnostic codes up through 2017, a follow-up of about 50 years. They adjusted all outcomes for age, race, education, and various health factors known to affect a woman’s AD risk.

Overall, 36 percent of the cohort developed dementia, but a woman’s risk dropped the more children she had. Compared to women with one child, those with three or more had a 12 percent lower risk. Estrogen levels surge during pregnancy, Gilsanz noted. On the other hand, having even one miscarriage boosted the odds of dementia by 25 percent. A late onset of puberty or early onset of menopause, leading to a short reproductive period, increased risk even more, by 31 and 28 percent, respectively. In general, every additional year in a woman’s reproductive span lowered her odds of AD by 2 percent, Gilsanz said.

The findings suggest that the more estrogen a woman is exposed to during her lifetime, the better her brain fares, Gilsanz said. On the other hand, miscarrying may indicate an unfavorable hormonal milieu, or other underlying health problems, she suggested.

The evidence suggests that estrogen strongly protects women’s brains before the age of 50, but does so only moderately between the ages of 50 and 59, and perhaps becomes harmful at age 60 and after, Walter Rocca of the Mayo Clinic in Rochester, Minnesota said in Chicago.

Another small study of women’s reproductive health drew a different conclusion. Molly Fox, University of California, Los Angeles, analyzed a case-control cohort of 133 women between the ages of 70 and 100 in England, half of whom had been clinically diagnosed with dementia. Fox looked for any correlation between reproductive history and dementia, and found that the more months a woman had been pregnant in her lifetime, the less likely she was to have dementia. Each additional month of pregnancy reduced risk by 5 percent, Fox reported in Chicago. If this was due to estrogen exposure, lower risk should correlate with the number of third trimesters, when estrogen spikes, Fox reasoned, but she found no such relationship. Instead, the number of first trimesters appeared protective, with each additional one lowering AD risk by about 30 percent (Fox et al., 2018). 

Why might that be? During the first trimester, the body boosts the number of regulatory T cells that suppress immune reactions to lower the odds of rejecting the fetus. If this immunosuppression persisted long-term, Fox suggested, it might limit inflammatory damage late in life. Inflammation contributes to AD and other neurodegenerative diseases. “Pregnancy may reorganize the body in ways that protect against AD later,” Fox said. She acknowledged her tiny study serves mostly as a stimulus to do this kind of analysis in larger cohorts, with examination of immune biomarkers. Intriguingly, a recent study found that microglia in aging female mice change their gene expression more than do microglia in aging males, strengthening the idea that the immune system may contribute to the female vulnerability to dementia (Aug 2018 news).—Madolyn Bowman Rogers

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References

News Citations

  1. Do Brain Changes at Menopause Make Women More Prone to Alzheimer’s?
  2. Dementia Risk Increases, at Least in Those Who Start Hormone Therapy Late
  3. Hormone Replacement Therapy Latest Entry to AlzRisk Database
  4. Early Hormone Therapy Does No Cognitive Harm
  5. Estrogen Therapy Could Hold Back Alzheimer’s, Shrink the Brain?
  6. ApoE: Common Microglial Culprit in Aging, Alzheimer’s, and Tauopathy?

Webinar Citations

  1. Not Dead Yet: Estrogen Deserves Another Chance

Paper Citations

  1. Espeland MA, Brinton RD, Hugenschmidt C, Manson JE, Craft S, Yaffe K, Weitlauf J, Vaughan L, Johnson KC, Padula CB, Jackson RD, Resnick SM, WHIMS Study Group. Impact of Type 2 Diabetes and Postmenopausal Hormone Therapy on Incidence of Cognitive Impairment in Older Women. Diabetes Care. 2015 Dec;38(12):2316-24. Epub 2015 Oct 20 PubMed.
  2. Gleason CE, Dowling NM, Wharton W, Manson JE, Miller VM, Atwood CS, Brinton EA, Cedars MI, Lobo RA, Merriam GR, Neal-Perry G, Santoro NF, Taylor HS, Black DM, Budoff MJ, Hodis HN, Naftolin F, Harman SM, Asthana S. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med. 2015 Jun;12(6):e1001833; discussion e1001833. Epub 2015 Jun 2 PubMed.
  3. Bromberger JT, Kravitz HM. Mood and menopause: findings from the Study of Women's Health Across the Nation (SWAN) over 10 years. Obstet Gynecol Clin North Am. 2011 Sep;38(3):609-25. PubMed.
  4. Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP, ELITE Research Group. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016 Mar 31;374(13):1221-31. PubMed.
  5. Kantarci K, Lowe VJ, Lesnick TG, Tosakulwong N, Bailey KR, Fields JA, Shuster LT, Zuk SM, Senjem ML, Mielke MM, Gleason C, Jack CR, Rocca WA, Miller VM. Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition. J Alzheimers Dis. 2016 May 7;53(2):547-56. PubMed.
  6. Fox M, Berzuini C, Knapp LA, Glynn LM. Women's Pregnancy Life History and Alzheimer's Risk: Can Immunoregulation Explain the Link?. Am J Alzheimers Dis Other Demen. 2018 Dec;33(8):516-526. Epub 2018 Jul 30 PubMed.

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