The Effects of Hormone Replacement Therapy on Alzheimer’s Disease

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Nathaniel Chin: Welcome to Dementia Matters, a podcast created by the Wisconsin Alzheimer's Disease Research Center. It's our goal to humanize Alzheimer's research so that our community, our patients, our participants at anyone else interested, can get a better understanding of the work that's happening to fight back against this disease. My name is Nathaniel Chin and I'm a geriatric and memory clinic physician at the University of Wisconsin. I'm also the family member of someone living with dementia. I'll be serving as your host for this podcast and asking the questions I believe on the minds of many in our community. Thanks for joining us.

Welcome to Dementia Matters. Today, I have Dr. Carey Gleason, an associate professor of medicine and geriatrics and gerontology with the University of Wisconsin School of Medicine and Public Health. Dr Gleason is an expert on cognitive effects of postmenopausal hormone therapy and health disparities in Alzheimer's disease. Thank you, Dr. Gleason, for being here this morning on Dementia Matters.

Carey Gleason: Happy to be here.

Chin: Well, Dr. Gleason, we know that women are at higher risk of developing dementia and the reasons for this are still being explored, but estrogen is thought to possibly be a factor. So why estrogen?

Gleason: A colleague and friend of mine once said that estrogen is a powerful molecule and it is indeed unique. There are receptors for estrogen throughout the body. So it doesn't have just one single action. So it works in our heart. It works on our bones. It works in our brain. So estrogen with these multiple activities throughout the body, it's not surprising that huge fluctuations in this molecule at the time of menopause would have systemic effects, and possibly long-term effects.

Chin: Now, prior studies have been done looking at estrogen hormone replacement therapy, and they showed that it was actually dangerous to women. And in particular I'm referring to the Women's Health Initiative, this big study that was done. What did that study show?

Gleason: So actually to simplify it in a single word as dangerous, is actually an oversimplification. I wouldn't put it that way. It had a very complicated profile of effects. Not surprising. Importantly, they used a form of hormone therapy that was the most common hormone therapy used at the time that was derived from pregnant mare's urine. So it's a non-human form of hormone therapy that was historically developed when we were unable to synthesize estrogen in the lab. So this form of hormone therapy was the most widely used so of course, they studied it in the Women's Health Initiative. So there was a huge panel of plus minus of the findings. So not surprisingly, it was very effective to prevent bone loss. So there is a benefit. However, there were some downsides. It surprisingly, it did not reduce the risk of dementia like they thought it would. It did not reduce the risk for cardiovascular disease like they thought it would. And it increased the risk for breast cancer, but only one form of hormone therapy did, the estrogen plus progesterone. However, if they took, women who were hysterectomized, took Premarin without the addition of medroxyprogesterone. So they looked at oral conjugated equine estrogens, equine as in horse -- use of that alone did not raise the risk for breast cancer. Only the combination of Oral CEE plus medroxyprogesterone acetate increased the risk of breast cancer. So again, this is very complicated profile plus minus. Bottom line is that it did not have the benefits that we thought it would, and it still had those risks, again, like we anticipated.

Chin: I think you highlighted the really important issue which is that hormone replacement therapy can be taken in multiple ways. There's many different versions of it, and clearly that matters.

Gleason: It does, and the really unfortunate thing is we've not attempted to synthesize or to replicate what has happening premenopausal. So think about this, a woman's cycle, actually, the hormone levels of progestin and estrogen are cycling throughout the 28 day cycle. We've never attempted to mimic that. We've simply just given a bolus of estrogen and a bolus of medroxyprogesterone acetate, which is again a non native form of progestin, and we've just administered this big bolus of estrogen and non-human or a synthesized progestin. So naturally, not surprisingly, we shouldn't be surprised that these didn't have the actions that a premenopausal naturally cycling estrogen did.

Chin: Well, so the science is imperfect and that's okay, I mean that's why we do this. But lots of studies have happened since this big WHI, this Women's Health Initiative, including one of yours called KEEPS.

Gleason: Yeah, so Dr. Asthana and I did this as an ancillary study to the primary KEEPS study led by Mitch Harmon. He was at Kronos Longevity Institute in Arizona. The KEEPS stands for kronos early estrogen prevention study. So not only did we, after the Women's Health Initiative, we were left with the question of the form of hormone therapy, but also the administration of it, how do we do this, do we do this orally, do we do this transdermally? And then secondly, or thirdly I should say, the important question of when to administer it. So one of the findings that came out of the Women's Health Initiative Memory Study, which was also an ancillary study to the Women's Health Initiative, looked at the risk for dementia. It was found that hormone therapy as administered in the Women's Health Initiative increased the risk of dementia. And the important finding, or the important design issue around that finding, was the fact that women enrolled in that ancillary study were age 65 and older. So there is actually no clinical reason to start women aged 65 years and older on hormone therapy.

Chin: Wow.

Gleason: But it was done for design reasons because you wanted to weight the risk for dementia in this group, so you wanted to pick those women who are at greater risk for dementia, in order to have more events to track. Classic design issue. So women enrolled in the Women's Health Initiative Memory Study were all over the age of 65 and administering hormone therapy to those women increase the risk for dementia, possibly because you have a system that's already destabilized due to the aging process due to insulin resistance, all sorts of factors that could play into it. Importantly, when they went back and looked at the women who were age 55 and first started on hormone therapy in the same study, the Women's Health Initiative, they didn't see an increased risk for dementia. So the timing was a major issue. So the Kronos Early Estrogen Prevention Study, early estrogen, we started the therapies within three years of their last menstrual period. So those women who started therapy within three years of their last menstrual period, either a premarin form, an oral CEE, plus a native form of progestin, and we also tested estradiol. So again, estradiol is the native form of estrogen in a woman's body.

Chin: The most natural way of doing it.

Gleason: Exactly. And again, a natural progestin. We found that there were no cognitive effects for these women. Wow. But we did find that there were mood benefits.

Chin: So not the negative and even a little bit of positive things.

Gleason: Yes. For one formulation, ironically it was for the oral CEE, there was mood benefits for the conjugated equine estrogen.

Chin: Well, that's a huge finding that really challenges the big prior one, that shows that there's maybe something else to looking at this.

Gleason: Yes. Yeah. It's just the bottom line is it's complicated for women who are seeking guidance on what to do at menopause, what do I do about these hot flashes? What do I do about these symptoms that are keeping me up at night or I feel like I'm out of control of my emotions, cognitively I feel foggy. Can they take hormone therapy as a, at least time important remedy for those symptoms? Our findings and findings of colleagues suggests that this is actually, it's a window of time that seems to be safe and we do know it benefits women's bone health and the sexual side effects and possibly mood effects.

Chin: So this a huge therapeutic opportunity for people, which makes sense to me, now knowing that you just received, you and your Co-PI, a $10.6 million dollar grant from the NIA. First of all, congratulations.

Gleason: Thank you.

Chin: That's huge. And it is a continuation of this project, this KEEPS. So what will you look at with this new project?

Gleason: So we're going to follow these women who are enrolled in KEEPS, in the original KEEPS, follow up with them 10 to 12 years after they were randomized. So after randomization, they were on therapy for four years. After that, we don't know if they themselves sought out therapy from their own doctor, or if they discontinued altogether. We're going to follow up because we do know what they were on at menopause and we're going to follow up with a number of brain imaging studies to really look at what it does for Alzheimer's disease pathology. Our preliminary data suggests that form of therapy is important in terms of what happens to amyloid deposition and possibly brain volume.

Chin: Wow. This is very exciting, and I'm hoping we'll be able to have you back on when you have your preliminary results.

Gleason: Yeah, I mean this is I think again, for any woman facing the menopausal transition, or in it, just having some clear cut guidelines for what do we do? Can we take therapy? Is this going to have long-term ramifications for our brains and how do we, how do we proceed?

Chin: Well, so you really asked the question that I wanted to ask. At this current time, what do we say to women in menopause, about to go into menopause, about hormone replacement therapy?

Gleason: So if you were taking it for reasons that are important during that menopausal transition. You're having hot flashes and you're worried about bone loss, the sexual side effects, there is enough data from three trials, the KEEPS included, and the Women's Health Initiative, and also our colleague Victor Henderson, looked at the similar type of question, the data suggests that it's safe. That it's safe for women to use hormone therapy at the menopausal transition. The remaining questions are what are the long-term effects, other questions related to the length of time. We're at a range of basically four to five years, and then the risks for breast cancer start to increase after that. So for safety reasons, a window of time, it's safe. That's the bottom line.

Chin: And I think that's not something everyone knows about it, so I'm glad you're able to share that with us and I'll be able to convey that onto my patients in clinic. Dr. Gleason, thank you so much for coming on Dementia Matters.

Gleason: Yeah, you're welcome.

Chin: Is there anything else that you want the community, particularly the women of the community, to know about estrogen and they're thinking.

Gleason: We're working on this. We're going to try to come up with some answers to guide women's health choices. This is a huge question for women.

Chin: All right. Stay tuned.

Gleason: Yes, indeed.

Chin: Alright, thank you.

Credits: Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center. The Wisconsin Alzheimer's Disease Research Center combines academic, clinical, and research expertise from the University of Wisconsin School of Medicine and Public Health, and the Geriatric Research Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. It receives funding from private, university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers. This episode was produced by Rebecca Wasieleski and recorded and edited by Alex Wehrli. Our musical jingle is "Cases to Rest," by Blue Dot Sessions. Check out our website at adrc.wisc.edu. You can also follow us on Twitter and Facebook. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.