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New Debate on Hormone Replacement Therapy and Dementia Risk

New Debate on Hormone Replacement Therapy and Dementia Risk

Hormone replacement therapy (HRT) is a common treatment for menopausal symptoms [1]. Current guidelines recommend that it be used at the lowest dose, for the shortest duration possible, and not past the age of 65 in order to minimize risks to brain and cardiovascular health [2]. New research, however, suggests that menopause and its symptoms can persist for over a decade in some women [3] and that long-term HRT may not pose serious risks to your brain [9]. With this in mind, do the treatment guidelines need to change?

The research on HRT and cognitive function paints a complex and somewhat contradictory picture. In 1986, one of the earliest HRT trials found that women with dementia taking estradiol showed significant improvements in attention, orientation, mood, and social interaction [4]. But this study only included seven patients and no control group.

Based on these and other promising findings, the Women's Health Initiative Memory Study (WHIMS) launched in 1991. It included over 4,500 postmenopausal women and examined the effects of estrogen plus progestin HRT on the incidence of dementia and mild cognitive impairment [5]. It found that HRT did not improve cognitive function, and it increased dementia risk for postmenopausal women over the age of 65. Study participants were, on average, 72 years old and approximately 15 years post-menopause when they started hormone therapy [5]. And, the hormone formulation used in the study was synthetic rather than bioidentical.

Two later randomized controlled trials addressed some of the issues with WHIMS by enrolling women closer to the onset of menopause and examining synthetic versus bioidentical hormones. The KEEPS trial included 662 women with an average age of 52.6 years. It found that neither type of hormone benefited cognitive function [6], though in women who carried the APOE4 gene, bioidentical hormones were associated with lower levels of beta-amyloid plaques (i.e., a hallmark of Alzheimer's) in the brain compared with synthetic hormones or placebo [7]. The ELITE trial compared healthy women within 6 years versus those over 10 years after menopause taking bioidentical hormones. It also found no evidence of cognitive benefit or harm in either group [8]. These studies only lasted four to five years, which isn't long enough to assess Alzheimer's risk.

But an observational study that followed 8,195 women aged 47–56 years for 20 years found that women who only used HRT for a short period after menopause did not have a lower risk of Alzheimer's disease, while treatment lasting over 10 years was associated with decreased risk [9]. This study is not conclusive as it was not designed to prove that HRT causes the decreased risk of Alzheimer's. It is possible that the women who chose to continue HRT were healthier in general than those who didn't.

Based on the available evidence, starting hormone replacement therapy within a few years of menopause presents little cognitive risk (or benefit) [6][8][10-13]. Although it is possible that HRT used past age 65 may reduce Alzheimer's risk if treatment is initiated during the critical window around the onset of menopause and continued for over 10 years [9], protection with long-term treatment has not been confirmed in randomized controlled trials yet.

As with any medication, there are some risks with HRT. It has been associated with small increased risks of heart attack, stroke, deep vein thrombosis, and breast cancer. The North American Menopause Society states: "Provided that the woman has been advised of the increase in risks associated with continuing hormone therapy beyond age 60 and has clinical supervision, extending hormone therapy use with the lowest effective dose is acceptable under some circumstances" [14]. If you do choose HRT, see your physician regularly and consider bioidentical rather than synthetic hormones.

  1. Gass ML, Maki PM, Shifren JL et al. (2015) NAMS supports judicious use of systemic hormone therapy for women aged 65 years and older. Menopause 22, 685-686.
  2. North American Menopause S (2012) The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 19, 257-271.
  3. Avis NE, Crawford SL, Greendale G et al. (2015) Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med 175, 531-539.
  4. Fillit H, Weinreb H, Cholst I et al. (1986) Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer's type. Psychoneuroendocrinology 11, 337-345.
  5. Shumaker SA, Legault C, Rapp SR et al. (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 289, 2651-2662.
  6. Gleason CE, Dowling NM, Wharton W et al. (2015) Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med 12, e1001833; discussion e1001833.
  7. Kantarci K, Lowe VJ, Lesnick TG et al. (2016) Early Postmenopausal Transdermal 17beta-Estradiol Therapy and Amyloid-beta Deposition. J Alzheimers Dis 53, 547-556.
  8. Henderson VW, St John JA, Hodis HN et al. (2016) Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology 87, 699-708.
  9. Imtiaz B, Tuppurainen M, Rikkonen T et al. (2017) Postmenopausal hormone therapy and Alzheimer disease: A prospective cohort study. Neurology .
  10. Gibbs RB, Gabor R (2003) Estrogen and cognition: applying preclinical findings to clinical perspectives. J Neurosci Res 74, 637-643.
  11. Maki PM (2013) Critical window hypothesis of hormone therapy and cognition: a scientific update on clinical studies. Menopause 20, 695-709.
  12. Sherwin BB (2009) Estrogen therapy: is time of initiation critical for neuroprotection? Nat Rev Endocrinol 5, 620-627.
  13. Zhang QG, Han D, Wang RM et al. (2011) C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-alpha and the critical period hypothesis of estrogen neuroprotection. Proc Natl Acad Sci U S A 108, E617-624.
  14. North American Menopause S (2015) The North American Menopause Society Statement on Continuing Use of Systemic Hormone Therapy After Age 65. Menopause 22, 693.

Yuko Hara, PhD, is Director of Aging and Alzheimer's Prevention at the Alzheimer's Drug Discovery Foundation. Dr. Hara was previously an Assistant Professor in Neuroscience at the Icahn School of Medicine at Mount Sinai, where she remains an adjunct faculty member. Her research focused on brain aging, specifically how estrogens and reproductive aging influence the aging brain's synapses and mitochondria. She earned a doctorate in neurology and neuroscience at Weill Graduate School of Medical Sciences of Cornell University and a bachelor's degree in biology from Cornell University, with additional study at Keio University in Japan. Dr. Hara has authored numerous peer-reviewed publications, including articles in PNAS and Journal of Neuroscience.

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