Affiliations of authors: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SST, SAM, WCW, GAC, SEH); Department of Epidemiology, Harvard School of Public Health, Boston, MA (SST, SAM, WCW, GAC, SEH); Department of Obstetrics, Gynecology, and Reproductive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SAM, RLB); Department of Nutrition, Harvard School of Public Health, Boston, MA (WCW)
Correspondence to: Shelley S. Tworoger, PhD, Channing Laboratory, 181 Longwood Ave., 3rd Floor, Boston, MA 02115 (e-mail: nhsst{at}channing.harvard.edu).
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ABSTRACT |
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INTRODUCTION |
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Therefore, we conducted a prospective, nested casecontrol study within the Nurses' Health Study (NHS) to examine the association between plasma concentrations of estradiol, free estradiol, testosterone, free testosterone, and sex hormonebinding globulin (SHBG) and postmenopausal breast cancer risk among women using PMH at blood collection. We assessed whether the associations differed by duration or type of PMH use and by various tumor characteristics, such as estrogen receptor (ER) and progesterone receptor (PR) status. We also examined the association between PMH use status and sex hormone concentrations.
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SUBJECTS AND METHODS |
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The NHS cohort was established in 1976 when 121 700 U.S. female registered nurses, aged 3055 years, completed and returned a mailed questionnaire. The NHS cohort has been followed every 2 years since inception by questionnaire to update exposure variables and to ascertain newly diagnosed disease. Data have been collected on various breast cancer risk factors, such as weight, height, age at menarche, parity, age at first birth, age at menopause, postmenopausal hormone use, and family history of breast cancer.
Between May 1989 and December 1990, 32 826 cohort members provided blood samples; women were between 43 and 69 years old at blood collection. Informed consent was obtained from each participant, and both the blood collection and this study were approved by the institutional review board of the Brigham and Women's Hospital. Details about the blood collection methods have been published previously (14). In brief, women arranged to have their blood drawn and shipped with an icepack via overnight courier to our laboratory, where it was processed and separated into plasma, red blood cell, and white blood cell components. Seventy percent of blood samples were collected while fasting for more than 8 hours, and 97% were received within 26 hours of collection. The stability of estradiol, testosterone, and SHBG in whole blood on ice for 2448 hours has been shown previously (15). Samples were stored in continuously monitored liquid nitrogen freezers after processing was completed at our laboratory. At blood collection, women completed a short questionnaire that asked about current weight, recent use of PMH (within the last 3 months), and the type of hormone preparation. Because our blood study questionnaire asked about recent PMH use, we estimated how many women were likely to have been taking PMH at blood collection by whether the woman reported that she had menstrual cycles caused by taking PMH at the time of blood collection or reported the use of PMH on the 1990 main NHS study questionnaire. We estimated that more than 90% of women reporting recent PMH use were using PMH at blood collection. Follow-up of the blood study cohort was 99% in 2000.
Case and control subjects were postmenopausal at the time of blood collection. Women were considered to be postmenopausal if they reported having a natural menopause (e.g., no menstrual cycles during the previous 12 months), had a bilateral oophorectomy, or had a hysterectomy but had at least one ovary remaining, and were at least 56 (for nonsmokers) or 54 (for smokers) years of age. These were the ages at which natural menopause occurred for 90% of the overall cohort.
Case subjects had no reported cancer diagnosis before blood collection and were diagnosed with breast cancer after blood collection but before June 1, 2000. In all, 461 case subjects (54 with in situ disease) of postmenopausal breast cancer among women using PMH at blood collection were reported and confirmed by medical record review (n = 453) or by verbal confirmation of the diagnosis by the nurse (n = 8). Because of the high confirmation rate in medical record review (99%), these latter case subjects were included in the analysis. Time from blood collection to diagnosis ranged from 1 to 151 months (mean = 67.3 months). Control subjects were matched by age (±2 years), month/year of blood collection (±1 month), time of day of blood draw (±2 hours), and fasting status (10 hours since last meal, <10 hours since last meal, or unknown), and had not developed breast cancer before the diagnosis date of their matched case. Exact control subject matches were obtained for 98% of case subjects for age, 95% for time of day of blood collection, and 94% for month of blood collection. One control subject was matched per case subject. We excluded four case subjects and two control subjects who were later determined to have an unknown menopausal status. Eleven control subjects went on to subsequently develop breast cancer; however, we included these individuals only as control subjects. This left 446 case subjects and 459 control subjects for analysis.
To compare sex hormone concentrations between PMH users and nonusers, we compared the 459 control subjects with 363 control subjects not taking PMH at blood collection. These latter control subjects were taken from a prospective nested casecontrol study of postmenopausal breast cancer among non-PMH users (2).
Laboratory Assays
Estradiol and testosterone were measured at Quest Diagnostic's Nichols Institute (San Juan Capistrano, CA) by sensitive and specific radioimmunoassay, after organic hexaneethyl acetate extraction and Celite column partition chromatography, as described in detail elsewhere (16). SHBG was assayed at the Reproductive Endocrinology Unit Laboratory at the Massachusetts General Hospital with the AxSYM Immunoassay system (Abbott Diagnostics, Chicago, IL). Free estradiol and free testosterone were calculated by the law of mass action as described by Sodergard et al. (17).
All pairs of casecontrol samples were assayed together, in random sample order. Laboratory technicians were blinded to casecontrol status. All samples for this casecontrol study were assayed between April and June 2004. Assays for women not using PMH were performed in two batches conducted between January and March 2002 (n = 185) and between October and December 2003 (n = 178). Fifteen samples from these two batches were included with the samples from the PMH users to assess laboratory drift over time. Intraclass correlations for all hormone concentrations between assay batches ranged from 0.82 (testosterone) to 0.97 (estradiol). In each batch, we included replicate plasma samples to assess laboratory precision. The average intraassay coefficient of variation across the three batches was 8.9% for testosterone, 9.5% for estradiol, and 7.8% for SHBG. The assay detection limit for estradiol was 2 pg/mL and for testosterone was 2 ng/dL. When plasma hormone values were reported as less than the detection limit, we set the value to half the limit (estradiol [n = 6] and testosterone [n = 8]).
Statistical Analysis
We identified statistical outliers by using the generalized extreme studentized deviate many-outlier detection approach (18). This analysis resulted in the removal of two testosterone and three SHBG values. Further, some assays could not be conducted because of low sample volume or technical difficulties with the assay.
To compare hormone concentrations between control subjects using and control subjects not using PMH at blood collection, we used linear regression of log-transformed hormone concentrations to estimate geometric means between the two groups, adjusting for body mass index (BMI) at blood collection (linear), age at menopause (<45, 4549, 5054, or 55 years), age at blood draw (<55, 5559, 6064, or
65 years), alcohol consumption (none, >05 g/day, or >5 g/day), number of ovaries removed (none/one or both), and time of blood collection (after midnight to 9 AM, after 9 AM to noon, after noon to 4 PM, or after 4 PM to midnight). We assessed whether there was an interaction between PMH use at blood collection and BMI (<25, 25 to <30, or
30 kg/m2) with an F test. We also categorized PMH users by duration of use at blood draw (<5 or
5 years, to mimic previous analyses of PMH and breast cancer risk), and type of hormone use (oral premarin [conjugated equine estrogens only], vaginal estrogen, or oral estrogen plus progestin). Too few women used a transdermal patch to be considered separately, and so we excluded them from this secondary analysis.
To test for differences in hormone levels between case and control subjects, we used mixed-effects regression models for clustered data to adjust for possible confounding due to the matching factors. For the primary analysis of breast cancer risk among PMH users, we used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) comparing quartiles (using the distribution of the control subjects) of sex hormone concentrations (18). The odds ratios appropriately estimate the relative risks (RRs) because the outcome is rare; therefore, we henceforth use the term "relative risk." In addition, we estimated relative risks and 95% confidence intervals comparing quartiles of sex hormone concentrations for various case subject groups (in situ versus invasive, ductal versus lobular, tumor size 2 cm versus >2 cm, ER/PR status, and time between blood collection and diagnosis) using polytomous unconditional logistic regression adjusting for matching factors (19). To determine whether the relative risks for case subject groups differed, we used the likelihood ratio test (19) to compare a model holding the association of log-transformed hormone levels and breast cancer constant across case subject groups to one allowing the association to vary. We also stratified by type of PMH use (estrogen-only pill, cream, or patch; estrogen-plus-progestin pill or patch; estrogen pill [Premarin]; estrogen-plus-progestin pill), PMH use status in the questionnaire cycle before diagnosis/reference date, age at blood collection, BMI, and time since menopause using unconditional logistic regression adjusting for matching factors. We also stratified by duration of current PMH use at blood collection, because a single plasma hormone level may be more reflective of long-term estrogen exposure among women using PMH for many years. Because our data suggested that hormone levels while taking PMH may reflect hormone levels while not taking PMH (e.g., BMI was associated with sex hormone concentrations in PMH users), we also stratified by the amount of time not using PMH between initiation of menopause and blood collection. Tests for heterogeneity (Pinteraction) were determined with the Wald test.
All models were adjusted for the following a priori potential confounders: BMI at age 18 years (<21, 21 to <23, 23 to <25, or 25 kg/m2), family history of breast cancer (yes or no), age at menarche (<12, 12, 13, or
14 years), age at first birth/parity (nulliparous, age at first birth <25 years and one to four children, age at first birth 2529 years and one to four children, age at first birth
30 years and one to four children, age at first birth <25 years and five or more children, or age at first birth <25 years and five or more children), age at menopause (<45, 4549, 5054, or
55 years), history of benign breast disease (yes or no), duration of oral contraceptive use in months (linear), duration of PMH use in months (linear), and type of PMH use (estrogen only or estrogen plus progestin). Tests for trend (Ptrend) were conducted by modeling log-transformed sex hormone concentrations continuously and using the Wald test (20). All P values were based on two-sided tests and were considered statistically significant if P
.05.
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RESULTS |
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DISCUSSION |
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We observed a wide range of hormone concentrations among women using PMH at blood collection, which is consistent with two studies that reported a large interindividual variability in response to PMH use (12,13). Kraemer et al. reported that the average within-person change in estradiol concentrations over 4 days of therapy with a transdermal patch ranged from 25 to 168 pg/mL. Interestingly, breast cell proliferation in women using PMH was observed to be correlated with estradiol concentrations ( = .54) (13). Several long-term studies have reported that sex hormone concentrations stabilize after about 2 months of PMH use (2123); this result is consistent with our data that hormone levels generally were similar in longer-term (>5 years) versus shorter-term users.
Oral estrogen only and estrogen plus progestin, but not vaginal estrogen cream, were associated with increased concentrations of estradiol, free estradiol, and SHBG, modestly higher testosterone, and a decreased concentration of free testosterone compared with nonPMH users. These changes are expected because estrone sulfate, a major component of many oral PMH preparations, can be converted in the body to estradiol and estrone. Our results are comparable to those of randomized trials and observational studies of PMH use that have reported increases in estradiol (12,13,2127), SHBG (12,13,2127), and free estradiol (22,23) and decreases in free testosterone (13,22,26). Unlike our study, previous reports did not observe increases in testosterone concentrations; however, the difference in testosterone between PMH users and nonusers in our study was relatively small compared with the differences for the other hormones.
In general, we did not find an interaction between PMH use and BMI with respect to sex hormone concentrations. It is particularly interesting that BMI was positively associated with estradiol, free estradiol, and free testosterone, and inversely associated with SHBG in both nonPMH and PMH users. The lack of interaction between BMI and PMH use with respect to hormone levels suggests that the importance of BMI in determining sex hormone levels is not diminished substantially in women using exogenous hormones; this result is somewhat inconsistent with studies reporting that BMI is more strongly associated with risk of breast cancer among nonPMH than among PMH users (2832). However, we found a relatively weak association of estradiol with breast cancer overall in PMH users, suggesting that the further elevation of estradiol attributed to high BMI in PMH users does not substantially influence breast cancer risk.
The associations we observed among PMH users between concentrations of estradiol and free estradiol and risk of breast cancer generally were of a lesser magnitude than those observed among nonPMH users in the NHS cohort (2) and in a pooled analysis of nine cohort studies that included the NHS (1). Studies in nonPMH users generally report a doubling in breast cancer risk associated with women with the highest quantile of estradiol and free estradiol compared with those with the lowest quantile, whereas we found a 30% and 70% increased risk associated with estradiol and free estradiol, respectively, among PMH users.
Several possible hypotheses could account for the differences in association between estradiol and breast cancer risk in PMH users versus nonusers. Data from previous studies have shown that there is not a strong doseresponse relationship between PMH dose and breast cancer risk (5,33). Therefore, if the doseresponse curve between sex hormone concentrations and breast cancer risk begins to plateau at high hormone concentrations, the lower risk estimates in PMH users may be due to their already high estrogen levels. Another hypothesis is that plasma estrogen concentrations in PMH ever users may not reflect long-term estrogen exposure as well as in never users, which is supported by the fact that the risk estimates for past and current users are similar (1,2). However, two observations in our study indirectly imply that estrogen concentrations in women using PMH are at least modestly associated with their estrogen levels when not using PMH. First, even among PMH users, there was a positive association between estrogen concentrations and BMI; body fat is the primary source of endogenous estrogen production in postmenopausal women. Second, the association between estradiol levels and breast cancer risk was strongest in women who spent the least amount of time taking PMH during menopause and who were leanest. These observations also may suggest that endogenous hormone exposure most strongly predicts breast cancer risk among women with the lowest cumulative estrogen exposure after menopause. Alternatively, because most PMH preparations contain many forms of estrogen, it is possible that the role of estradiol and free estradiol in promoting breast cancer decreases in importance in PMH users. For example, conjugated equine estrogens, common in most PMH preparations in high levels, and estradiol have a similar proliferative action on breast cancer cells (34). Clearly, more research is needed to better understand the underlying biology of the association between estrogen and breast cancer risk in PMH users.
In the NHS cohort, we observed that estrogen concentrations were most strongly associated with ER+/PR+ breast cancers among both PMH users and nonusers, although again the risk estimates were attenuated in the PMH users versus nonusers (for a 10-pg/mL unit increase in estradiol, RR = 1.5, in nonPMH users, and RR = 1.1, in current PMH users) (data not shown). Among PMH users, we found an interaction between estrogen levels with age and BMI that was not observed in nonPMH users (2). Specifically, the association between estrogen and breast cancer risk was stronger in older PMH users, which is consistent with a few studies suggesting that the association between BMI and breast cancer is stronger in older women (31,35,36). However, our finding may be related to the longer duration of PMH use in women older than 60 years (mean = 10.3 years) versus those 60 years or younger (mean = 6.2 years). We also found that the association between estrogen and breast cancer risk was stronger in lean PMH users (BMI < 25 kg/m2), which is consistent with reports that PMH increases breast cancer risk more in lean women than in obese women (7,10,29,37). The influence of estrogen may be weakest in obese women because other factors associated with obesity, such as insulin resistance (38), may increase risk of breast cancer. However, because such interactions were not observed in never or past PMH users in our cohort (2), these results should be interpreted with caution.
Breast cancer risk estimates for testosterone, free testosterone, and SHBG in PMH users were similar to those found in nonPMH users in previous studies (1,2), although the estimate for testosterone in our study was slightly lower than the pooled estimate from nine cohort studies (1). Interestingly, unlike for estrogens, studies in nonPMH users have not reported different associations in never and past users for testosterone and SHBG. Thus, PMH use does not appear to influence the association between testosterone/free testosterone or SHBG and breast cancer, even though PMH use is associated with a sharp increase in SHBG and a decrease in free testosterone levels. For both SHBG and free testosterone, these data imply that the risk associations are linear across large concentration ranges. Unlike the results in nonPMH users in the NHS cohort (2), we did not see differences in associations for these hormones by ER/PR status among PMH users; however, the results are qualitatively similar for PMH users and nonusers.
This study has several strengths and limitations. First, all case and control subject samples for PMH users were assayed at the same time, which reduces variability in hormone outcomes, but the assays for control subjects not using PMH were conducted at a different time from samples from women using PMH, possibly affecting the comparison of hormones between users and nonusers. However, a subset of samples assayed at both times had a high intraclass correlation, suggesting that the timing of the assay batches likely did not substantially affect our results. Second, the assays we performed had excellent coefficients of variation and were highly reproducible. However, it is possible that the assay for estradiol may have cross-reacted with unconjugated equine hormones, although this effect is probably small. Third, we had a large number of case subjects for the primary analyses, which increased our power to detect statistically significant associations, but our sample size for subanalyses (e.g., invasive versus in situ disease) was more limited. Further, the case and control subjects in this study reported using PMH within the previous 3 months, so it is conceivable that some women were not using PMH at the exact time of blood collection, which could attenuate our results. However, on the basis of other questionnaires completed around the time of the blood collection, we estimate that more than 90% of women were using PMH at the time of the blood collection.
To our knowledge, this is the first prospective epidemiologic study of plasma sex hormone concentrations and breast cancer in women using PMH. We found that plasma sex hormone concentrations were associated with breast cancer risk among PMH users, although not all risk estimates were statistically significant. The testosterone and SHBG associations were of similar magnitudes to those observed among women not taking PMH, whereas estradiol associations were substantially weaker. However, free estradiol was positively associated with risk of postmenopausal breast cancer.
Validation of these results in other studies could lead to a refinement for risk prediction models among women using PMH. Identifying factors that are associated with endocrinologic responses to exogenous hormones may elucidate subgroups of women who are at particularly increased risk of breast cancer from PMH use.
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NOTES |
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Manuscript received October 29, 2004; revised January 19, 2005; accepted February 15, 2005.
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