The menopause hormone replacement debate: what I am doing as an APOE4 gene carrier at risk of Alzheimer’s

Picture of Dr. Jen Kerns

Dr. Jen Kerns

If you caught my blog last week, you know that I had stopped taking my birth control pills for about 9 days before my yearly OB-gyn appointment in the hopes of getting labs drawn to help figure out how far into perimenopause or menopause I am. Well, it turns out that my OB-gyn says that you can’t get an accurate assessment of the body’s innate hormone levels within the first few weeks of going off of oral contraceptive pills, because the body’s hormone production can be falsely suppressed by birth control for up to 3 months. So she said she could check my labs if I wanted, but it wouldn’t really be meaningful unless I stayed off my OCPs for 3 whole months and then checked. Given that I was having so much more insomnia being off the pill, I just wasn’t willing to suffer through 3 more months of that just to get my labs checked. She said she could switch me to hormone replacement therapy at any time, that you don’t have to wait for actual menopause, and that the only reason she uses oral contraceptives instead of hormone replacement for perimenopausal women is for the pregnancy prevention benefit. For me, I am not worried about pregnancy. I am worried about Alzheimer’s.

As I wrote about last week, there is evidence that the menopause transition is a time in a woman’s life when her brain is suddenly more vulnerable, and brain imaging studies have shown that there are dramatic changes in the structure and function of women’s brains as they go through perimenopause and menopause. Among Alzheimer’s researchers and prevention experts there is a theory — the “critical period hypothesis” — that initiating hormone replacement therapy at the time of menopause or soon thereafter may be neuroprotective. This has not been proven, and the research thus far is complex and somewhat contradictory. Initiating hormone replacement too many years after menopause may actually have a detrimental effect, as was seen in the landmark Women’s Health Initiative Memory Study (WHIMS). This was a huge clinical trial of over 4500 postmenopausal women which randomized women to receive hormone replacement therapy or placebo, with the hypothesis that hormone replacement would provide cognitive benefits. WHIMS showed that beginning hormone replacement therapy in older women (the age of study participants was, on average, 72 years old) and approximately 15 years post-menopause not only fails to protect against dementia or cognitive decline, but substantially increases the risk of dementia. The specific hormones used were conjugated equine estrogens (estrogen derived from horses) with or without medroxyprogesterone acetate (a synthetic progesterone-like compound), depending on whether the woman had an intact uterus. Several important questions remained unanswered after WHIMS, including: 1. Does initiating hormone replacement in younger women (in perimenopause and/or within the first 5 years of menopause) have more benefit?, 2. Does the use of bioidentical estradiol and progesterone differ from the use of animal-derived or synthetic hormones?, and 3. Do women carrying the APOE4 gene have a different response to hormone therapy than noncarriers? (APOE epsilon4, also known as APOE e4 or APOE4, is a gene known to confer an increased risk of Alzheimer’s Disease, and I found out through 23andMe that I do have one copy of it).

Does it matter if I take synthetic hormones in the form of birth control pills vs. hormones exactly as they exist in our bodies naturally (also known as “bioidentical” hormones)? I don’t know. The evidence is far from conclusive, but there is some suggestion in the current medical literature that synthetic forms of estrogen and progesterone, such as ethinyl estradiol and norethindrone acetate (the two hormones in my oral contraceptives), or conjugated equine estrogens and medroxyprogesterone (the hormones in Premarin and Prempro, which were the drugs used in WHIMS) may confer more risk than bioidentical hormones. This study in rats (mind you, rats are not humans, so take this with a grain of salt!) suggests that synthetic estrogen in the form of ethinyl estradiol may reduce the number of cholinergic cells in the basal forebrain, and may affect spacial memory and reference memory during the learning phase of testing in maze challenges. Meaning, ethanol estradiol may have negative effects on brain cells and on learning and memory in rats. And as I mentioned above, WHIMS showed harm with the use of horse estrogens and synthetic progestins in older women.

Another observational study found that earlier age at initiation of menopausal hormone replacement therapy, particularly before menopause, was associated with less evident brain aging in APOE4 carriers like me, but not in non-carriers. This study’s findings lend more support for the “critical period hypothesis” which suggests that hormone replacement may be neuroprotective (at least in APOE4 carriers) if it is initiated near the time of cessation of ovarian function, within about 5 years of menopause — but it’s just an observational study, which means that you can’t infer causation from it. Only a randomized clinical trial can show causation.

This is excerpted from a succinct summary of relevant medical literature including randomized clinical trials on the website of the Alzheimer’s Drug Discovery Foundation:

“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.”

PiB SUVR is the quantification of beta amyloid in the brain using a PET scan. This image is from the aforementioned KEEPS clinical trial. APOE4 carriers showed less amyloid in their brains when they took hormone replacement.

See how confusing the current scientific findings are? We just don’t know for sure (yet) whether hormone replacement therapy helps or harms. So for now, I am taking my chances. I know that I sleep like hell when I am off hormones, whether they be synthetic ones like in my previous oral contraceptives or bioidentical ones, so I want to be on something. And I just have a gut feeling that bioidentical hormones maybe be safer (and could potentially be helpful in APOE4 carriers like me), so that’s what I’m switching to instead. I am less than a week in, and the last 2 nights I finally slept well again for the first time in a few weeks since stopping my birth control pills. Until more research is done, I can only hope that I am doing my brain good.

On a separate note, I’m here to stay accountable with my progress toward my weight goal of 135 pounds, which I still aim to reach. In fact, next week I’ll be back to talk about some extremely exciting developments in my Alzheimer’s prevention efforts (hint: I spoke to the nation’s leading expert on Alzheimer’s prevention!!) which are leading me to double down on my weight loss efforts. In the meantime, here are my current weight loss numbers (this week I lost 2 pounds!):

Project 135 stats:

Starting weight: 159.6 (May 2020)
Week 1: 157.2
Week 2: 155.6
Week 3: 155.4
Week 4: 153.8
Week 8: 150.8
Week 12: 150.8
Week 17: 155.2 (after sugar binges)
Week 19: 153.8
Week 25: 146.6
Week 26: 148.2 (after Halloween candy)
Week 28: 146.6
Week 29: 148.8 (after Thanksgiving)
Week 30: 148.4
Week 31: 149.0
Week 32: 152.2
Week 33: 153.0 (after Christmas)
Week 37: 153.8 (January 2021: Started intuitive eating experiment)
Week 38.5: 160.8 (on Feb 1, 2021 -> the experiment failed! Go back to NSNF)
Week 40: 156.4
Week 42: 151.6
Week 44: 153.0
Week 45: 154.4
Week 46: 152.4

Total weight loss: 7.2 pounds (4.5%)

Stay well until next week, my friend, and happy Spring! 🌸
Love, Jen




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