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 men^15,16 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.