Health & Medical Menopause health

Exposure to Hormones and Adjuvant Therapy for Breast Cancer

´╗┐Exposure to Hormones and Adjuvant Therapy for Breast Cancer

Discussion


Our findings indicate that, before beginning adjuvant therapy, postmenopausal women with breast cancer have poorer cognitive function than age- and education-matched healthy postmenopausal women. These results are similar to other studies that reported poorer pretreatment cognitive function in women with breast cancer. Our results also indicate that factors related to lifetime hormone exposure influence cognitive function in postmenopausal women. However, the influence of these hormone exposure factors on cognitive function did not differ between healthy postmenopausal women and postmenopausal women with breast cancer before the initiation of systemic adjuvant therapy. Therefore, these results do not explain the poorer pretreatment cognitive function observed in postmenopausal women with breast cancer.

It seems reasonable to speculate that lifetime hormone exposure would be related to cognitive function. The influences of sex steroids on cognitive function are well documented; they begin prenatally and seem to persist throughout life. We first hypothesized that factors associated with less estrogen exposure (shorter reproductive life and parity) are associated with poorer cognitive function, particularly verbal memory, in women with breast cancer compared with healthy women. In general, our findings support the hypothesis that factors associated with less estrogen exposure predict poorer cognitive function, although these hormone exposure factors did not predict poorer verbal memory as we postulated. Furthermore, these findings were not limited to our breast cancer group.

We found that greater number of pregnancies predicted poorer psychomotor efficiency in the overall sample. Others have found a significant negative relationship between the number of pregnancies and cognitive function. McLay et al found that, compared with parous women, nulliparous women had better cognitive function, as measured by the Mini Mental State Examination (╬▓ = -0.83, P = 0.02). Sobow and Kloszewska found that greater number of pregnancies was associated with a younger age of onset of Alzheimer's disease (r = -0.065, P < 0.01).

It is not clear why we did not see a significant relationship between the number of pregnancies and cognitive function in our breast cancer group or control group. There was no difference in the number of pregnancies between study groups. It is possible that this variable was highly correlated with other variables in the regression model such that it became nonsignificant when considered jointly with the other variables.

When we computed partial correlations between the duration of reproductive life and cognitive factors, we did not find any significant relationships; thus, this predictor was not entered into the regression models for further evaluation. However, we found that greater number of years since menopause met our screening criteria and was found to be a marginally significant predictor of poorer executive function in the overall and breast cancer groups, compared with better visual learning and memory in the breast cancer group. In addition, greater number of years since oophorectomy was related to poorer psychomotor efficiency in our overall sample.It is not clear why we observed divergent findings related to time since menopause and visual learning and memory versus executive function. Ryan et al also found that younger age at menopause (P = 0.05) was associated with poorer executive function in 996 healthy postmenopausal women. They found no relationship between age at menopause and visual learning and memory or any other cognitive domain.

We also hypothesized that factors associated with greater estrogen exposure (oral contraceptive use and HT use) would be associated with better cognitive function, particularly verbal memory, in women with breast cancer. Our findings related to this hypothesis are conflicting. We did find that factors related to oral contraceptive use predicted better verbal memory and attention, but these findings were not limited to the breast cancer group. Interestingly, we found that factors related to HT use predicted poorer attention; again, these findings were not limited to the breast cancer group.

We found that a history of oral contraceptive use predicted better verbal memory and attention in the overall and breast cancer groups. Greater years since oral contraceptive use predicted poorer verbal learning and memory in the control group, and poorer attention in both the control group and the breast cancer group, suggesting that exposure to exogenous estrogen with oral contraceptive use may benefit verbal memory and attention later in a woman's life. There have been previous studies of cognitive function with oral contraceptive use, although these studies were conducted in samples of women who were current oral contraceptive users. Silber et al and Grinspoon et al found that current oral contraceptive use was not related to cognitive function. Mordecai et al compared verbal memory between young women who were naturally cycling (n = 16) and young women who were current oral contraceptive users (n = 20) and found no changes in verbal memory in the naturally cycling women. However, better verbal memory was observed during the active phase of oral contraceptive use (P < 0.05) among women who were current users, and verbal learning and memory was better during the active phase than the inactive phase (P < 0.0001).

The synthetic estrogen used in oral contraceptives has not changed over time; however, the progestin formulations used in oral contraceptives have changed, and earlier preparations are different from progestins in current use. We did not have data on the type of oral contraceptive preparation that the women in our study had received in the past and, thus, were not able to examine the potential differential effects of the types of oral contraceptive preparations on cognitive function.

Interestingly, we observed that a longer duration of exposure to another form of exogenous estrogen (HT) predicted poorer attention in all of our study groups. Shumaker et al found no cognitive benefit with HT after a large randomized controlled trial; in fact, their findings also suggest that HT may be detrimental to cognitive function. However, results of several observational studies point to a beneficial role for HT in cognitive function among younger women. The basis for this contradictory evidence may be a consequence of methodological differences across studies. The study conducted by Shumaker et al included women who were at least 65 years of age, older than the mean age of women beginning HT and older than the mean age of women in many observational studies. There is speculation that the cognitive benefits of HT may be best derived when it is taken during the menopausal transition or in the early years of menopause.

Differences in age at the time of exogenous estrogen exposure may also explain the fact that past oral contraceptive use was related to better cognitive function in our study, but longer duration of HT use was related to poorer cognitive function later in life. Studies have demonstrated that there is an increased risk of ischemic stroke with HT. There is also an increased risk of stroke with oral contraceptive use, particularly in smokers. Ethinyl estradiol (EE) used in oral contraceptive preparations is very different from estradiol. Similarly, conjugated equine estrogens used in some HT preparations are also very different from EE and estradiol. Both EE and conjugated equine estrogens increase the risk for stroke and venous thromboembolism, whereas transdermal estradiol or endogenous estradiol of ovarian origin does not increase the risk for stroke. Women with a documented history of stroke were excluded from participation in our study. However, it is possible that women in our study did experience undetected thrombogenic events and that women exposed to exogenous estrogen in the form of an oral contraceptive at a younger age were more resistant to these events than women exposed to exogenous estrogen with HT use at an older age.

Our findings lend support to the theory that greater lifetime hormone exposure is related to better cognitive function. However, the fundamental question about the basis for poorer pretreatment cognitive function in women with breast cancer remains. The basis for poorer pretreatment cognitive function is probably multifactorial and may include persistent effects of surgical operation and anesthesia, mood, sleep problems, concomitant medications, and tumor-related factors. Previous investigators have examined factors that may influence cognitive function before adjuvant therapy. Wefel et al found that, although not significant, women who were postmenopausal, had no prior HT use, and have had lumpectomy/mastectomy were nearly twice as likely to be cognitively impaired compared with women without these characteristics. However, Ahles et al found that, compared with women who exhibited normal cognitive performance, women categorized as exhibiting "lower-than-expected cognitive performance" did not differ in age, education, menstrual status, surgical operation type, anesthesia duration, HT use, thyroid function, complete blood count, platelet count, vitamin B12 level, and folate level.

Results of our study and those of others suggest that neither depression nor anxiety explains the poorer pretreatment cognitive function observed in women with breast cancer. Sleep problems may exist in women with breast cancer at pretreatment, a time when they are still adjusting to their cancer diagnosis and anticipating therapy. Data suggest that sleep problems are associated with poorer cognitive function in other populations; however, these relationships have not been examined in women with breast cancer.

This study has some limitations; thus, caution must be exercised in interpreting these findings. Medical record data were used to acquire some information related to estrogen exposure factors; thus, the accuracy of this information cannot be assured, and we did not have complete information on the specific types of oral contraceptives or HT preparations taken by women. The breast cancer and control groups differed with respect to age and estimated verbal intelligence. However, the mean difference in age and estimated intelligence was 1.76 years and 3.64, respectively, and these are not probably clinically meaningful differences. Moreover, we controlled for age and estimated verbal intelligence in our analyses. Finally, the size of our control group was smaller than that of the breast cancer and overall groups. This may explain the fact that there were fewer significant correlations between cognitive function and hormone exposure factors in the control group. Most of the correlations observed in the control group were in the same direction as what was observed in the overall and breast cancer groups, and the strength of the associations was within the same range.

The strengths of this study include the use of a comprehensive battery of neuropsychological measures that assessed multiple cognitive domains. Our sample was composed exclusively of postmenopausal women and included a matched control group of healthy women.

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