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Inhibitors of estrogens may influence cognitive function in postmenopausal breast cancer survivors.

Breast cancer, one of the two most common forms of cancer, accounts for about 30% of newly diagnosed cancers. About one in eight women in the United States will develop invasive breast cancer (cancer that has grown into healthy tissue) at some point in her life. In 2018, over a quarter million women are expected to be diagnosed with this disease. The vast majority of those cancers have estrogen receptors (ERs), which predicts that estrogens promote growth of the tumors. The standard post-surgery treatment to decrease the risk of recurrence is to deprive the cancer cells of estrogens. In postmenopausal women, two types of drugs accomplish this: (1) selective estrogen receptor modulators (SERMs; sometimes called anti-estrogens or estrogen antagonists; e.g., tamoxifen), drugs that bind to ERs and block estrogens’ effects in some cells; and (2) aromatase inhibitors (AIs), drugs that block the production of estrogens throughout the body. This article will focus on the latter type of drug.

Many women taking these drugs may not be aware of the potential negative side effects, and others may have experienced them, but not realized that they are due to these drugs that interfere with the normal function of estrogens. Before taking these drugs, postmenopausal women should ask some very important questions. What are the potential negative side effects? Are the drugs essential for women with a low absolute risk of recurrence? Only an oncologist can inform a woman of her absolute risk of recurrence; this article will discuss one of the potential negative side effects, bearing in mind that not all women respond in the same way to these drugs.

Although we generally think of estrogens as being made in the ovaries and declining at menopause, they are also produced in adipose (fat) tissue, placenta, the adrenal gland, liver, heart, skin, and even the brain. Although production of estrogens by the ovaries stops after menopause, adipose tissue and the brain continue to produce them. Estrogens produced in the brain should be taken into account when considering the side effects of AIs taken to inhibit production of estrogens.

Unlike the case with women, we have decades of laboratory research that has informed us of what estrogens do in laboratory animals that can inform us of the possibilities in women. In laboratory animals, estrogens influence a variety of behaviors and brain functions, including sexual behavior, maternal behavior, anxiety-like behaviors, depression-like behavior, pain sensitivity, and sleep. Estrogens also influence cognitive function (including learning, memory and attention), and they protect the brain against damage or impairment of function.

Most women know that estrogens act on their breast and uterus, and that they influence hot flashes and bone density. However, although there has been much less research on women, estrogens also have many other positive effects on quality of life by their actions on the brain as is the case in laboratory animals.

Determining estrogens’ effects on cognitive function in women is more complicated than in laboratory animals; however, they definitely enhance some aspects of cognitive function, and their decrease after menopause may contribute to the decline in verbal memory in some women. Use of estrogens is also associated with a decreased risk for Alzheimer’s Disease and other non-brain-related side effects like joint pain.

The effects of estrogens on cognitive function have been somewhat controversial. That is because not all studies have confirmed effects of estrogens on cognitive function in women. However, those studies that failed to confirm the effects had a number of design problems. To understand the reason for the discrepancies, it is instructive to consider the features of experiments that have most consistently observed positive effects of estrogens. (1) Treatment with estrogens typically begin during or soon after perimenopause. (2) The skin patch containing estradiol (the specific, dominant hormone from the more general class of hormones called “estrogens” in women) tends to be more effective than orally administered Premarin™, which contains a wide variety of estrogens purified from horse urine. (3) Verbal memory, the principal cognitive domain influenced by estrogens, was assessed. (4) The picture is much clearer with estradiol alone, not estradiol combined with various progestins (the class of hormones, which includes the specific, dominant hormone in women, progesterone).

AIs reduce brain estradiol levels in laboratory animals. In mice and rats, these inhibitors of estrogen synthesis alter areas of the brain where estrogens influence cognitive function. Because an AI infused directly into the brain inhibits some aspects of memory, we know that estradiol produced in the brain is essential for some aspects of cognitive function.

Although the research on the effects of antiestrogens in laboratory animals is straightforward and easy to interpret, unfortunately, the results of experiments looking at the role of AIs on cognitive function in women are much more complicated. There have been reports of positive, negative, and absence of effects, most likely due to the limitations and confounding factors of this type of experiment in women.  

Many of the confounding factors in human experiments that confuse interpretation of the results are controllable, such as specific type and dose of drug, age of participants, and time since menopause. However, unlike laboratory animals where a researcher can order a few dozen nearly identical mice from a supplier, finding groups of women in which all of these factors are similar is difficult, costly, and maybe even impossible. Consequently, many of the experiments had mixed groups with women receiving a variety of treatments. Furthermore, many of the experiments did not focus on the cognitive domain that we know is most influenced by estrogens in women—verbal ability. Many of the factors that are difficult to control, but potentially confounding, may cancel out or obscure effects. These factors include the cognitive reserves (i.e., the cognitive abilities at the start of treatment) of the women, compliance with dosing, life histories, individual differences in the body’s ability to break down drugs, and diet. Sarah Berga, Chair of Obstetrics and Gynecology at Wake-Forest Baptist Medical Center, has suggested that the effects of AIs on cognitive function may be particularly obvious in women with lower cognitive reserves to begin with.

Each of the studies on the effects of AIs on cognitive function in women suffered from at least one limitation. However, taken as a whole and combined with what we have learned about the effects of these drugs by studying laboratory animals, we have sound basis for suggesting that AIs are likely to have negative side-effects on some aspects of cognitive function in some women. This is consistent with the fact that estrogens, including those produced in the brain, have positive effects on cognitive function; therefore, we expect AIs to block that production, and therefore have negative effects on cognitive function. Further, although this article has focused on cognitive function, because estrogens also have other effects in the brain, including on mental health (e.g., depression), sexual desire, and sleep, we must consider the possibility that AIs interfere with these as well.

Unfortunately, because the state of our knowledge about the side effects of AIs in women is limited, we cannot answer all the questions about the side effects of these drugs at this time. However, the decision of whether or not to take an AI to decrease the likelihood of recurrence of breast cancer must include consideration of the potential negative side effects on quality of life. Nevertheless, because many of the effects of estrogens and antiestrogens in the brain are conserved between laboratory animals and humans, our decisions should be informed by the vast amount of research in laboratory animals.

The decision to use an AI should be made with full awareness of potential negative effects on cognitive function (and other side effects). AIs have effects on cognitive function in laboratory animals, and the weight of evidence is consistent with effects on at least one cognitive domain in women—verbal abilities. As with any treatment for any disease, women should weigh the potential negative consequences of taking the drug against the absolute risk of not taking the drug.

To make an informed decision, breast cancer survivors should speak with an oncologist who is fully aware of the negative, as well as the positive, effects of inhibitors of estrogens. Of course, if absolute risk of recurrence of the cancer is high, the potential risk of negative side effects on the brain balanced against the decreased probability of recurrence would likely be worth it. However, if absolute risk is quite low, a woman working with her oncologist may decide that the risk of potential side effects is not worth it.

Finally, awareness of potential side effects is the most important factor. If a woman taking AIs notices something is amiss (and many women have had this concern), she should speak up to her doctor. Together, they should be able to decide if what she feels is due to the drug, and if so, if there are possibilities of alternatives.


Photo Credit: Alexander Raths, "Doctor explaining diagnosis to his female patient," via Shutterstock, 27 April 2018.