Does hormone therapy for breast cancer affect the brain?

By Jeffrey D. Bbottle blurlaustein, PhD

 An important treatment for many breast cancer patients – called hormone therapy, or what I call anti-hormone therapy for reasons that will become clear  – may have side effects that impact brain function – an issue that often gets overlooked.

The vast majority of breast cancers (60-80%) contain estrogen receptors (ERs), so they are referred to as ER-positive. Treatment for ER-positive breast cancer aims to block estrogens in one way or another. These treatments are referred to as hormone therapy.

ER-positive breast cancer patients may get hormone therapy for different reasons. For post-menopausal women, they may be given this treatment after surgery to try to keep the cancer from coming back. In premenopausal women, treatment is typically an estrogen receptor blocker.

While hormone therapy can be effective, as with most drugs, it may also cause possible side effects that can affect quality of life, which you and your oncologist should consider when choosing (or not-choosing) treatment.

An often-overlooked, and also understudied, side effect of hormone therapy is its negative impact on the brain. Research has shown that estrogen-blocking treatments may have a variety of side effects on the brain including possibly increasing the likelihood of depression and anxiety and decreasing verbal memory and fluency.

One possible reason for this is that estrogens do positive things for the brain; so taking medication that blocks estrogens may be stopping them from doing the good things they typically do, such as:

influencing mood, including protecting against depression and anxiety
regulating sexual desire (libido)
impacting executive function, including the ability to make decisions, plan, and more
helping with sleep quality
playing an important role in some aspects of cognitive function, like talking clearly
being neuroprotective, which means that they slow the aging of the brain and may even protect against Alzheimer’s Disease
protecting against hot flashes, because the absence of estrogens is responsible for hot flashes

Aromatase inhibitors and the brain

Let’s talk about the aromatase inhibitors (e.g., Arimidex, Aromasin, Femara ), drugs that block the production of estrogens throughout the body, including in the ovaries, fat tissue, and brain.

As with most drugs, there are potential side effects of these drugs. For example, many women taking aromatase inhibitors have to deal with stiff, painful joints as a side effect. Although it’s not certain why the joint pain occurs, lower levels of estrogens are likely to play a role.  Some health care professionals expect and listen to complaints about joint pain, but may know much less about the effects of these drugs on the brain.

Although few clinical studies focus on brain-related effects, we know that loss of estrogens can influence cognitive function, including verbal memory and fluency; can increase the likelihood of depression, anxiety, and sleep disturbances; and can lead to the loss of interest in sex.  There is also evidence that it increases the risk of Alzheimer’s Disease.

Tamoxifen and the brain

When women can’t tolerate the side effects of an aromatase inhibitor, they will typically be switched to a different aromatase inhibitor or an anti-estrogen drug, like tamoxifen, and premenopausal women are likely to start with tamoxifen.

Tamoxifen is an interesting drug, insofar as it mimics the effects of estrogens in some tissues, such as bone, where it protects bone mass, while blocking the effects of estrogens in the breast. It also increases the risk of developing uterine cancer.

All told, the loss or blockade of estrogens can result in a wide variety of brain-related symptoms. In the post-surgical breast cancer survivor, some of these can be confused with effects of surgery or radiation.

Of course, it must be noted that not every woman will respond in the same way to these drugs.

Why my wife decided not to do hormone therapy

I will relate a personal story to explain one possible approach to decision-making. My wife had a small ductal breast cancer that fortunately did not spread to the lymph nodes. In addition to extensive radiation treatments following her lumpectomy, her oncologist prescribed an aromatase inhibitor.

As a neuroendocrinologist, I expressed concern about blocking the positive effects of estrogens throughout the body, including the brain. The oncologist’s response was that she had prescribed the drug to many women, but only a few had complained of mood disorders like depression and anxiety. (One wonders how many patients had brain-related problems that they did not think of mentioning to the physician.)  She continued that not using the hormone treatment would double my wife’s risk of the cancer coming back.

As a scientist, I am an advocate of medicine that is informed by scientific research rather than by anecdotes. Therefore we sought a second opinion from another oncologist, who was more familiar with the scientific research on this topic. When I related to him that we were told that going off of the drug would double my wife’s risk of recurrence, he pointed out the difference between relative risk and absolute risk.

My wife’s first oncologist was correct that the risk would double — a frightening number; however, that was her relative risk. One also has to consider the absolute risk. In my wife’s case, stopping anti-hormone treatment would only raise her absolute risk from 2% to 4%.

With that information, my wife then had a choice that was not difficult to make when one considers the side effects of anti-hormone therapy.  Is that small a difference in risk worth the side effects of the drug? This is a question that every woman has to answer for herself, but every woman should know to ask her oncologist about the absolute risk for her particular situation.  Only then can the possible side effects be put into proper perspective.

I recently had a conversation with a friend who had been taking an aromatase inhibitor for three years after a lumpectomy. Although she was about to switch to tamoxifen because of side effects of the aromatase inhibitor, she insisted that her oncologist determine her absolute risk. When she discovered how low her risk was, she made the decision to stop treatment.

The bottom line

The weight of evidence from a variety of studies on the role of estrogens in the brain suggests that breast cancer survivors really should gather all the facts before starting on a treatment with drugs that block production or action of estrogens.

For patients, this may feel like a lot of information. The most important thing is to discuss all of the options with your oncologist. Decreased production, or “blockade,” of estrogens undoubtedly has a variety of side effects, but depending on your risk, the anti-hormone treatment may be the lesser of two evils.

Writer’s note: During this entry, I have used the term estrogens rather than the singular estrogen.  Estrogens refer to a class of hormones, of which estradiol is the most common hormone. There are other estrogens produced in the body (e.g., estrone, estriol), and there are estrogens present in the environment (e.g., estrogens found in plants, like soy).  As a neuroendocrinologist, I find the term “estrogen” too imprecise.  If we know the particular estrogen, I use the name of the hormone.  If we do not, or if the relevant hormone could be any estrogen, I use the term estrogens.

Guest blogger Dr. Blaustein is a professor in the Department of Psychological and Brain Sciences and Neuroscience and Behavior Program at the University of Massachusetts.

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