Disorders of Aging: March 2020

Why a Brain Doctor Asks About Hormone Replacement Therapy

Richard S. Isaacson, M.D.


Feb. 19, 2020 (medscape.com) – I’m Dr Richard Isaacson, director of the Alzheimer’s Prevention Clinic at Weill Cornell Medicine and NewYork-Presbyterian.

Hormone replacement therapy (HRT) for Alzheimer’s prevention is a loaded topic, around which there are a lot of differing opinions out there. Over the past 5 years, I can tell you that my own comfort level with discussing this topic has definitely evolved exponentially.

Five years ago, I wouldn’t have even wanted to talk about a topic like this because the data were all over the place. At that time, I may have been able to state one thing: HRT during the perimenopause transition may have some protective effect on the brain. I couldn’t say whether it’s protective against dementia, Alzheimer’s, or cognitive decline—just that taking HRT for 5-7 years during the menopause transition was okay. But I’d add, “I don’t know. I’m just a brain doctor. You should probably go see an ob/gyn.”

Guiding Patients Means Knowing What to Ask

Today, things are a little bit different. Now when I see a woman with a family history of Alzheimer’s disease at our program who wants to try to do anything to reduce her risk for dementia, I spend at least 10-15 minutes in the first hour-and-a-half visit just talking about HRT.

We talk about what her symptoms are. Is she having hot flashes? If so, I explain that hot flashes are not necessarily just an endocrine-related thing; it’s really a neurologic manifestation of a hormonal shift in the brain.

I take a pretty comprehensive history of the perimenopausal changes. When was the very first time she started having any symptom whatsoever? Is it night sweats? Is it mood changes? Is it something else?

I also don’t ask just about brain symptoms but about other symptoms that maybe neurologists don’t focus on too much: Is there vaginal dryness? Is there pain during intercourse? These are really important things to understand, because it helps me fine-tune my understanding of the underlying issues. I can hone in on whether there is a local problem of too little estrogen in the reproductive organs or whether it is just neurologic complaints.

When it comes to HRT, I don’t think we know exactly what the right treatment is. However, my general feeling, based on the evidence, being cautious, and wanting to do no harm, is that less is more. For example, is it really necessary to take a pill of estrogen when a very small dose of a cream or even a patch may give a smoother, more continuous delivery over time, which may in fact replicate the body’s natural process anyway? Based on my own gut instinct and reviewing the best available evidence on my own and in conversation with many ob/gyns and reproductive endocrinologists, a patch may be sufficient.

Does a person just need estrogen or perhaps progesterone as well? This requires taking a clinical history. Even though we’re an Alzheimer’s prevention clinic, we now look at hormones, estradiol, progesterone, and all sorts of different things. We obtain these baseline results and follow them over time, just as we track other objective measures. In addition to body composition (eg, fat levels or muscle mass), cognitive function, cholesterol levels, and metabolism, hormones are now one of the important puzzle pieces we consider.

Another aspect of this that we’re really just starting to look at is brain function. For example, what if a woman in the perimenopause transition has glucose hypometabolism, meaning reduced glucose activity in specific brain regions that are worrisome for the earliest phases of Alzheimer’s disease, even before they exhibit symptoms? Is that someone who I may want to pay more attention to from a hormone replacement perspective? If someone has normal brain metabolism versus impaired brain glucose metabolism, maybe that can give us a clue as to whether they need HRT, and if so, which specific type of treatment.

What Role Will HRT Play in the Future?

Although the jury is still out about some of these seminal questions, there has been a big difference in my response to hormone replacement as a potential protective intervention for Alzheimer’s prevention.

Now, I understand these idiosyncrasies. I understand that, in the future, whether it’s 2 or 10 years away, patients will get an examination, blood test, and perhaps a brain scan, followed by a conversation with their physician to really understand the specific aspects of hormone deficiency that may need to be replaced or balanced in an effort to protect brain function over time.

Also in a few years, when someone goes on HRT, aside from just getting a bone scan and perhaps responding to a questionnaire, they may also get a brain scan. By better understanding this, perhaps we can tell whether whatever variation or specific regimen of HRT the person was put on needs to be changed because cognitive function actually declined.

Take-Home Messages

I truly believe that the perimenopause transition is an exceptional window of opportunity in our fight against Alzheimer’s disease. Two out of every three brains affected by Alzheimer’s disease is a woman’s brain. Five to 10 years ago, I had no idea why. It’s not just because women live longer; it’s because hormone transition affects brain pathology, brain metabolism, and the person’s risk for Alzheimer’s disease.

Another key consideration is weighing the risks versus the benefits of HRT so we can get everyone on the same page. For example, if someone has a familial risk for breast cancer, or if the woman has actually had a stroke, a blood clot, or currently smokes, these are all things that increase the potential risks of using HRT. Also, what if a person is not using progesterone and she has her uterus? Maybe she will be increasing her risk for uterine cancer [because opposing estrogen with the addition of progesterone is protective and decreases the risk for endometrial cancer].

But overall, I would say the gestalt about HRT and its specific impact on women’s Alzheimer’s risk is that it’s an individual decision. One must balance the risks versus benefits, take into account the evolving evidence, and really consider the type, dose, method of delivery, and duration of the HRT. For example, in our practice, 5-7 years of HRT sounds reasonable, but does 10, 12, 15 years, or more? I’m not sure that we really know enough to have a one-size-fits-all approach to this.

In the next several years, I expect much new data to come from our research and from others’. I think, following that, we will have the recipe, algorithm, or at least a general set of recommendations for HRT to reduce Alzheimer’s risk.

Author: Richard S. Isaacson, M.D., Associate Professor, Department of Neurology, Weill Cornell Medicine, New York, NY
Disclosure: Richard S. Isaacson, has disclosed the following relevant financial relationships: Serve(d) as a scientific advisor for: Accera, Inc.

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