Estrogen, Tamoxifen, and the Brain
Authors: Patricia A Ganz, Steven A Castellon, Daniel H S Silverman
Journal: JNCI Journal of the National Cancer Institute (2002)

With the aging of the population and the increasing numbers of individuals that are being diagnosed with dementia or milder forms of cognitive dysfunction, there is heightened interest in identifying risk factors and protective factors for this important health problem. A series of recent publications (1–6) have called increased attention within the cancer community to the complaints of memory loss and decreased cognitive abilities from patients in active chemotherapy treatment, as well as of those who have received chemotherapy within the previous several years. The results of these studies (1–6) suggest that neurocognitive testing detects clinically significant, but sometimes subtle, abnormalities in a subset of patients who are exposed to both high-dose and standard-dose chemotherapy treatments. In this issue of the Journal, Ernst and colleagues (7) explored the association between the use of tamoxifen therapy in elderly breast cancer patients (mean age 70.4 years) and patterns of brain metabolism by comparing data from those patients with data obtained from an age-matched sample of healthy older women who had received hormone replacement therapy (HRT), largely as unopposed estrogen, and data from an age-matched sample of healthy older women who had never received HRT or tamoxifen. These investigators made use of a noninvasive neuroimaging tool, proton magnetic resonance spectroscopy, to measure the concentrations of specific biochemical markers in defined areas of the women’s brains. In this cross-sectional study, the authors hypothesized that the breast cancer patients who had received tamoxifen therapy would have higher cerebral concentrations of myo-inositol (MI), a compound previously implicated in glial metabolism, than would the healthy women who had not received tamoxifen. Thus, the level of MI was used as a marker to detect changes in brain chemistry associated with tamoxifen exposure. They examined three regions of each subject’s brain: the frontal white matter, the basal ganglia, and the left hippocampal region. All subjects were evaluated with physical examinations and laboratory tests to rule out the presence of any serious metabolic, psychiatric, or neurologic disorders. Brief cognitive testing, using a modified mental status examination and two tests of psychomotor speed, detected no statistically significant differences in cognition among the three groups of women. Although the authors did not report on the estimated levels of intellectual functioning in these women, educational attainment was similar for the three groups of women. Ernst and colleagues (7) found a statistically significant difference in cerebral MI concentrations among the three treatment groups (P .02). Whereas the overall concentration of MI was statistically significantly lower in the tamoxifen (P .01) and HRT (P .03) groups than in the control group, the authors found that the most pronounced difference in the MI concentration among the treatment groups occurred in the basal ganglia. In addition, they described an inverse relationship between the length of exposure to tamoxifen and MI concentrations in the basal ganglia and in the hippocampus. Based on these findings, the authors suggested that patients may have received neuroprotective benefits from tamoxifen and HRT, as evidenced by the lowered MI concentrations in their brains. Even if one were to accept the spectroscopy findings at face value, however, it is highly speculative to interpret them as indicative of neuroprotection. In fact, decreases in cerebral MI levels that are measurable by proton magnetic resonance spectroscopy are associated with a variety of processes, including nonspecific cerebral insults that result from exposure to ingested ethanol (8) or cirrhotic hepatic encephalopathy (9), the latter of which is completely reversed following liver transplantation. It is thus not even clear whether the decreased cerebral MI levels observed by Ernst and colleagues in the tamoxifen users are, in fact, a good thing, let alone specifically neuroprotective. Although the findings of Ernst et al. (7) are provocative and might be reassuring to the millions of women who have taken or are taking tamoxifen, one must be cautious about data that were obtained from a study that included only 16 elderly breast cancer patients who had received tamoxifen therapy. While these authors posit a benefit for study subjects who used either tamoxifen or HRT, it is important to consider alternative explanations for these results that take into account all of what we know about the physiologic effects of estrogen in women, as well as the relationship between lifelong exposure to estrogen and the risk for breast cancer (10–12). First, the observations of lower MI levels in the brains of women on tamoxifen and HRT in this study could reflect the lifelong exposures of these women to endogenous and exogenous estrogens, which may well have reduced the extent of glial cell proliferation in their brains. Specifically, it is well-established that older women who develop breast cancer have higher circulating levels of estrogen after menopause than healthy elderly women who do not have breast cancer (13), they have denser bones and, thus, a lower risk of osteoporosis (14,15), and they have greater breast density (10)—all of which are associations that reflect greater lifelong exposures to endogenous estrogens and, consequently, tissue responsiveness to the effects of estrogen. Thus, one wonders if the brains of the women with breast cancer in the Ernst et al. study were exposed to the beneficial effects of endogenous estrogens long before those women took tamoxifen. Similarly, compared with women who do not take HRT after menopause, those who do take HRT have higher circulating levels of estrogen, and as a result, their bones are protected from the development of osteoporosis, and they have denser breasts (16). These same women are at increased risk of developing breast cancer, such that each year of HRT use is equivalent to an additional year of menstrual life in