Blog

Jan 20th, 2021
By Dr. Rebecca Provorse

Menopause is a universal event for women who live to midlife. The transition from pre-menopause to post- has a long list of symptoms including a decrease in verbal memory1. It is this very symptom which causes great anxiety in many of my patients. They are concerned the memory lapses mark the beginning of cognitive decline, dementia or Alzheimer’s Disease. A large number of these menopausal women have cared for their parents with failing memory issues and know, first-hand, the burden it places on families.

Does memory loss in menopause signal such a disease? Are women more at risk? And, if so, is estrogen helpful to reduce incidence and/or risk?

Alzheimer’s disease (AD) is a progressive neurodegenerative condition that causes memory loss, cognitive deficits, and behavioral changes. AD dementia is the most common form of dementia, comprising 60 to 70 percent of all types. More than 5.8 million people in the United States currently have an Alzheimer’s diagnosis, and it is estimated that number will triple by 2050 unless new treatments or interventions to prevent or delay the onset of AD are identified2. With the aging of the population, the burden of this dementia on society is likely to be huge.

Risk factors for Alzheimer’s disease in women include age3, depression,4,5, hypertensive pregnancy disorders,6 insomnia,7 and low education8. We also know that early menopause (e.g., before the age of 40) --either natural or surgically-- has been associated with an increased risk of dementia.9

Research offers mixed opinion on incidence between men and women around the world, with some studies showing similar incidence between the sexes until the age of 80.10,11,12 Even if women and men have the same incidence of AD dementia, because the life expectancy for women is longer than for men, and age is the greatest risk factor, the lifetime risk of AD dementia is greater for women.13 In addition, the mechanisms, pathways, and risk factors can still differ. For example, hypertension during pregnancy is associated with cognitive decline later in life.14 Women have twice the risk of depression compared to men15,16 and that risk increases after onset of menopause, especially for women with pre-existing depression.17,18 Sleep apnea and poor sleep quality have been associated with cognitive decline and an increased risk of AD dementia19 and these are well-known to increase in incidence and severity with menopausal status.20

Menopause is the loss of reproductive function. With such, the main reproductive hormone in women, estradiol, declines to nearly immeasurable levels after the last menstrual period or (more rapidly) with surgical removal of the ovaries. Estrogens are involved in the health of numerous body systems. Relevant to this discussion, estradiol plays a significant role in overall brain health and cognitive function. From the developing fetus to the end of fertility, a female brain is influenced by this powerful steroid hormone, ranging from establishment of sex differences to pervasive growth and neuroprotective effects. Estradiol also impacts cellular physiology, gene expression, and enzymatic activity in the brain.21 Knowing that estrogens are important on the growth, regulation and maintenance of brain health might lead one to presume that the absence of such hormones would be associated with decline.

Does the research support this idea?

A number of independent studies have looked at specific areas of the brain playing major roles in learning and memory (e.g. the hippocampus, Broca’s area, etc). The research has compared those brain regions of pre- and postmenopausal women, using and not using estrogen replacement therapy (ERT). The findings show post- menopausal women using ERT have larger volumes in these areas than post-menopausal women who have never used estrogen therapy or even those who were past users.22,23 These structures express receptors for the sex hormone estradiol24 and giving estrogen replacement appears to protect against age-related atrophy.25

With respect to cognition, the research had been mixed for decades. A 1998 comprehensive review of 30 years of literature (1966-1997) with a meta-analysis on 10 studies of estrogen use in postmenopausal women suggested a 29% decreased risk of developing dementia among estrogen users.26 However, the authors of this review found the methodologies to be inconsistent enough for them to NOT recommend ERT for mitigating the risk of AD dementia in women. In 2001 the results from the Women’s Health Initiative Memory Study suggested that women who start estrogen therapy after the age of 65 (my emphasis) were at greater risk of dementia.27 Then in 2010 a review of more recent research concluded that the “critical period” hypothesis that had formed from the WHI was valid.28 The research now suggests “that the positive effects of estrogen are most robust in young women and in older women who had initiated ERT around the time of menopause.” And in 2019, the Menopausal Journal with its own literature review, reiterated that “there is a cognitive benefit from a longer reproductive window complemented with hormone therapy.29

In summary: the female brain is stimulated to develop and thrive in the presence of estrogens, especially estradiol. The functions of cognition, memory, sleep, emotional wellness as well - as the physical structures- are all maintained, in part, with the ebb and flow of estradiol in a healthy fertile adult woman. When that critical hormone declines, so does the health of the brain. Women in the US have a life expectancy average of 83 years.30 Living to that age means spending nearly half of one’s life without optimal brain function unless it is replaced. As research has defined a “critical period” to replace estrogen (for many health issues, including preventing dementia), starting ERT in perimenopause is an intelligent choice for a smart brain. And though all the research, thus far, has been on static ERT (same dose every day), it makes even more sense to me as a healthcare provider to optimize patient sex hormones levels the way they were at the patient’s healthiest state (eg in a rhythm, with potency and frequency at physiologic levels).

Dr. Rebecca Provorse is naturopathic physician who practices in Portland, Oregon and has been treating menopause with hormone therapies since 2004. In 2006, she became the first provider in Oregon to utilize Physiologic Restoration and it soon became her preferred method for treating menopause. She serves on the Women’s Hormone Network Board of Directors, speaks at the WHN annual conference and offers peer-mentoring to other health care practitioners who would like to adopt this methodology into their patient care.


References

  1. Epperson CN, Sammel MD, Freeman EW “Menopause effects on verbal memory: findings from a longitudinal community cohort” J Clin Endocrinol Metab 2013; 98:3829–3838
  2. Alzheimer’s Association: Alzheimer’s disease facts and figures. www.alz.org
  3. Fratiglioni L, Viitanen M, von Strauss E, et al. “Very old women at highest risk of dementia and Alzheimer’s disease: incidence data from the Kungsholmen Project, Stockholm” Neurology 1997; 48:132–138
  4. Ownby RL, Crocco E, Acevedo A, et al.: Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry 2006; 63:530–538
  5. Goveas JS, Espeland MA, Woods NF, et al. “Depressive symptoms and incidence of mild cognitive impairment and probable dementia in elderly women: the Women’s Health Initiative Memory Study” J Am Geriatr Soc 2011; 59:57–66
  6. Mielke, Michelle M PhD, “Sex and Gender Differences in Alzheimer’s Disease Dementia” Psychiatr Times. 2018 Nov; 35 (11):14-17.
  7. Lim AS, Kowgier M, Yu L, et al. “Sleep Fragmentation and the Risk of Incident Alzheimer’s Disease and Cognitive Decline in Older Persons” Sleep 2013; 36:1027–1032
  8. Karp A, Kareholt I, Qiu C, et al. “Relation of education and occupation-based socioeconomic status to incident Alzheimer’s disease” Am J Epidemiol 2004; 159:175–183
  9. Rocca WA, Grossardt BR, Shuster LT: Oophorectomy, menopause, estrogen treatment, and cognitive aging: clinical evidence for a window of opportunity. Brain Res 2011; 1379:188–198
  10. Fratiglioni L, Viitanen M, von Strauss E, et al. “Very old women at highest risk of dementia and Alzheimer’s disease: incidence data from the Kungsholmen Project, Stockholm” Neurology 1997; 48:132–138
  11. Letenneur L, Gilleron V, Commenges D, et al. “Are sex and educational level independent predictors of dementia and Alzheimer’s disease? Incidence data from the PAQUID project” J Neurol Neurosurg Psychiatry 1999; 66:177–183
  12. Matthews FE, Stephan BC, Robinson L, et al. “A two-decade dementia incidence comparison from the Cognitive Function and Ageing Studies I and II.” Nat Commun 2016; 7:11398.)
  13. Plassman BL, Langa KM, Fisher GG, et al.: Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 2007; 29:125–132
  14. Mielke MM, Milic NM, Weissgerber TL, et al.: Impaired cognition and brain atrophy decades after hypertensive pregnancy disorders. Circ Cardiovasc Qual Outcomes 2016; 9:S70–7
  15. Goveas JS, Espeland MA, Woods NF, et al. “Depressive symptoms and incidence of mild cognitive impairment and probable dementia in elderly women: the Women’s Health Initiative Memory Study” J Am Geriatr Soc 2011; 59:57–66
  16. Kessler RC, McGonagle KA, Swartz M, et al. “Sex and depression in the National Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence” J Affect Disord 1993; 29:85–96
  17. Freeman EW, Sammel MD, Liu L, et al “Hormones and menopausal status as predictors of depression in women in transition to menopause” Arch Gen Psychiatry. 2004;61(1):62-70.
  18. Cohen LS, Soares CN, Vitonis AF, et al. “Risk for new onset of depression during the menopausal transition: the Harvard Study of Moods and Cycles” Arch Gen Psychiatry. 2006;63(4):385-390.
  19. Lim AS, Kowgier M, Yu L, et al. “Sleep Fragmentation and the Risk of Incident Alzheimer’s Disease and Cognitive Decline in Older Persons” Sleep 2013; 36:1027–1032
  20. Dancey David R.MD, HanlyPatrick J.MD, et al “Impact of Menopause on the Prevalence and Severity of Sleep Apnea”. Chest, 2001; Vol 120; Is 1:pg 151-155.
  21. McCarthy, Margaret. “Estradiol and the Developing Brain” Physiol Rev 88: 91–134, 2008
  22. Lord C, Buss C, Lupien SJ, Pruessner JC “Hippocampal volumes are larger in postmenopausal women using estrogen therapy compared to past users, never users and men: a possible window of opportunity effect.” Neurobiol Aging. 2008 Jan; 29(1):95-101.
  23. Eberling JL, et al. “Preliminary evidence that estrogen protects against age-related hippocampal atrophy.” Neurobiol Aging. 2003 Sep; 24(5):725-32.
  24. Gibbs RB, Gabor R “Estrogen and cognition: applying preclinical findings to clinical perspectives.” J Neurosci Res. 2003 Dec 1; 74(5):637-43.
  25. Ibid.
  26. Yaffe et al. “Estrogen Therapy in Postmenopausal Women: Effects on Cognitive Function and Dementia” JAMA. 1998;279(9):688-695
  27. Shumaker SA, Legault C, Kuller L, et al. “Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study”. JAMA 2004; 291:2947–2958
  28. Craig, Michael and Murphy, DGM “Estrogen therapy and Alzheimer's dementia” Ann of NY Acad Sci 14 September 2010
  29. North American Menopause Society (NAMS) "Hormone therapy associated with improved cognition: New study demonstrates benefits of extended estrogen exposure and longer-term hormone therapy in battling cognitive decline." Menopause 16 October 2019.
  30. Roser M, Ortiz-Ospina M and Ritchie H “Life Expectancy” Our World In Data. 2013, rev 2019. https://ourworldindata.org/life-expectancy
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