Affiliations of authors: G. Ursin, A. Paganini-Hill, R. K Ross, M. C. Pike, Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles; S. London, National Institute of Environmental Health Sciences, Research Triangle Park, NC; F. Z. Stanczyk, E. Gentzschein, Department of Obstetrics and Gynecology, University of Southern California/Los Angeles County Women's Hospital. .
Correspondence to: Giske Ursin, M.D., Ph.D., Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Ave., MS #44, Suite 4407, Los Angeles, CA 90033.
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ABSTRACT |
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INTRODUCTION |
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The main circulating unconjugated estrogen in postmenopausal women is E1,
which is readily converted to E2. Two main pathways for metabolizing E2 are via 16-hydroxylation and 2-hydroxylation. The major estrogen metabolites are
excreted in urine in a conjugated form and include glucuronides and sulfates of the following
compounds: 2-hydroxylation products (2-hydroxyestrone [2-OHE1],
2-hydroxyestradiol, and 2-methoxyestrone), 16
-hydroxylation products (E3 and
16
-hydroxyestrone [16
-OHE1]), E1, and E2 (4). The roles of these estrogen metabolites have been the subject
of much discussion. The 16
-hydroxylated metabolites are biologically active (5,6). The extent to which the 2-hydroxylated metabolites are active or can form
active or genotoxic metabolites is controversial (7-10). However, some
investigators characterize 2-OHE1 as the "good estrogen" (11) and have suggested that the amount of estrogen that is metabolized via the
16
-hydroxylation pathway may be associated with the risk of developing breast cancer (12-14).
Epidemiologic data for this hypothesis are sparse. Two small studies found that the extent of
16-hydroxylation was higher in women with breast cancer (15) and
in women with a high familial risk of breast cancer (16) than in control
women. However, a third study (4) found no elevation of
16
-hydroxylation products in patients with breast cancer compared with control subjects. A
fourth study (17) found no important association between the ratio of
2-OHE1 to 16
-OHE1 and breast cancer when premenopausal and
postmenopausal women were considered together, but it found a strong inverse association when
data from the 23 postmenopausal patients and 28 postmenopausal control subjects were
compared. The control subjects in all of these studies were simply convenience samples. A recent
nested case-control study (18) reported an inverse association, but the
findings were not statistically significant and the confidence intervals (CIs) were wide.
We collected urine samples from participants in a previously conducted, population-based,
case-control study to determine whether postmenopausal women with breast cancer have a lower
ratio of urinary 2-OHE1/16-OHE1 than control subjects, as
proposed by the "good estrogen" theory. Previously, we (19) have reported unadjusted pilot results from the first 25 patients and 23 control
subjects that used an earlier version of the 2-OHE1 and 16
-OHE1
assay.
In this report, we present results from 66 patients and 76 control subjects. All samples were
analyzed with an updated version of the 2-OHE1 and 16-OHE1
assay.
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SUBJECTS AND METHODS |
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We included patients with breast cancer and control subjects who had previously participated
in a population-based, case-control study at the University of Southern California. Patients were
women with a diagnosis of breast cancer identified through the Los Angeles County Cancer
Surveillance Program (the Los Angeles National Cancer Institute Surveillance, Epidemiology,
and End Results [SEER]1 registry) who were
English-speaking residents of
Los Angeles County. Patients were diagnosed with breast cancer from March 1, 1987, through
December 31, 1989 (20), or from January 1, 1992, through December 31,
1992, were white (including Latina), and were born in the United States, Canada, or Western
Europe from 1923 through 1937. Control women were individually matched to patients by age
(±3 years), ethnicity (Latina/non-Latina), and neighborhood of residence. The response
rates in the first part of the study were 64% for patients and 80% for control
subjects (20). Written informed consent was obtained from all
participants. In this estrogen metabolism study, we targeted a subset of the patients and control
subjects from the parent study. We included only patients diagnosed with incident cancer
localized
to the breast as defined by the SEER summary staging (21) (tumor of any
size, confined to breast tissue and fat, and no distant metastasis). Additional eligibility criteria
were obtained from published data and discussions with experts in the field of 2-hydroxy and
16-hydroxy estrogen metabolism and are as follows: 1) no medications that might interfere
with estrogen metabolism within the previous 6 months (specifically, cimetidine, thyroid
supplements, estrogen or progesterone compounds, tamoxifen, or
-3 fatty acid
supplements); 2) never used cancer chemotherapeutic agents (22-25); 3)
no general anesthesia in the previous 3 months; 4) weight between 80 and 200 pounds (36 and 90
kg); and 5) nonsmoker for the past 3 years.
On the basis of data from the parent study, we identified 458 nonsmoking patients who weighed less than 200 pounds and 732 corresponding control subjects. We attempted to contact all of these women by telephone and/or letter to determine eligibility for this study. We were unable to contact 51 patients and 93 control subjects because they had moved and no forwarding address was available. An additional 19 patients and one control subject had died. Of the remaining 388 patients and 638 control subjects, we successfully contacted 312 (312/458 = 68.1%) patients and 329 (329/732 = 44.9%) control subjects. A large number of responders (211 patients and 220 control subjects) were found to be ineligible because of recent medication use (tamoxifen [144 patients], thyroid supplements [22 patients and 17 control subjects], chemotherapy or megestrol acetate [17 patients], estrogen [17 patients and 168 control subjects], or other medication [14 patients and 31 control subjects]), current weight of more than 200 pounds (nine patients and nine control subjects), recent general anesthesia (one patient and one control subject), or currently smoking (one patient). Fourteen patients and six control subjects met two exclusion criteria. Twenty-five eligible patients and 24 eligible control subjects refused to participate. In addition, we were unable to schedule urine collection for two patients before the study ended. We enrolled 74 patients and 85 control subjects. We subsequently excluded two additional patients and four additional control subjects because of incomplete risk factor information, one patient with in situ breast cancer, two patients with unknown disease stage, and three patients and five control subjects whose samples had very low urinary creatinine levels (<0.20 mg/mL). We present the results on the remaining 66 patients and 76 control subjects.
To each participant, we shipped a box containing a 100-mL urine vial with a 100-mg ascorbate tablet, a small cooler with an ice pack, an informed consent form, and a questionnaire on recent intake of medications, alcohol, and specific foods. We used a semiquantitative food-frequency questionnaire on their usual diet over the past 12 months (26,27) and asked the women to report their intake of alcohol and cruciferous vegetables during the 24- and 48-hour periods, respectively, before urine collection. The first morning urine samples were returned to us. All samples were frozen at -70 °C within 30 hours after collection. Samples, blinded for the case or control status, were shipped to two laboratories for analyses (see below). The urine collection was conducted from 1993 through 1996. Levels of estrogen metabolites did not differ by time since diagnosis in patients (data not shown).
Enzyme Immunoassay of 16-OHE1 and 2-OHE1
Measurements of urinary 16-OHE1 and 2-OHE1 were carried
out in the laboratories of H. L. Bradlow and D. Sepkovicz (Strang Cornell Cancer Research
Laboratory, New York, NY). Commercially available competitive enzyme immunoassay kits
(Estramet; Immuna Care Corporation, Bethlehem, PA) were used to measure 2-OHE1 and 16
-OHE1 directly in urine. High-affinity murine monoclonal
antibodies
specific for the estrogen metabolites were immobilized directly on microtiter plates, and the
enzyme alkaline phosphatase was linked to each estrogen metabolite, which was used to compete
with a standard or analyte in the assay. Each sample of urine was acidified and subjected to
ß-glucuronidase/aryl sulfatase hydrolysis before it was assayed (28).
These kits have been validated previously (28,29). Samples that had been
analyzed with a previous version of the assay (19) were assayed again
with the adjusted version that allowed for the lower estrogen values among postmenopausal
women. The intra-assay coefficients of variation were 15.7% for 2-OHE1 and
16.2% for 16
-OHE1.
Radioimmunoassay of Urinary E1, E2, and E3
Measurements of urinary E1, E2, and E3 were carried out in the laboratory of F. Z. Stanczyk (Los Angeles County/University of Southern California Medical Center) with high-performance liquid chromatography and radioimmunoassays (19). Each sample of urine was acidified and subjected to ß-glucuronidase/aryl sulfatase hydrolysis before it was assayed. The E1, E2, and E3 fractions were quantified by radioimmunoassay as described previously (30-32). Quality-control samples were included with each set of samples assayed to monitor assay reliability. The intra-assay coefficients of variation were 9.3% for E1, 16.8% for E2, and 13.6% for E3.
Statistical Analysis
All of the directly measured hormone variables were logarithmically transformed. The
statistical significance of the difference in these variables between patients and control subjects
was thus evaluated by use of t tests on the natural logarithms. We used logistic
regression to determine the odds ratio (OR) of breast cancer associated with various ratios of
urinary 2-OHE1/16-OHE1 and computed P values for
Mantel's test for trend (33). All P values are from
two-sided tests. Because this study did not maintain the matching of the original enrollment, we
used unconditional logistic regression but adjusted for the original matching variables [age,
ethnicity, and socioeconomic status based on area of residence (34)] and other potential confounders (33).
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RESULTS |
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Table 4 shows the geometric mean levels for 2-OHE1,
16
-OHE1, and the ratio 2-OHE1/16
-OHE1 by
selected risk factors. There were no remarkable differences in the estrogen metabolite ratios
across the levels of these risk factors; all of the CIs overlapped.
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DISCUSSION |
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Epidemiologic data addressing the 2-OHE1/16-OHE1
hypothesis are sparse. Schneider et al. (15) injected 33 perimenopausal
and postmenopausal breast cancer patients and 10 postmenopausal control subjects with E2 labeled with tritium in the 17
, C2, and 16
positions. They determined the
extent of oxidative metabolism at the different sites by drawing serial blood samples after the
isotope administration. Patients had 60% greater 16
-hydroxylation than did control
subjects; this difference was statistically significant. However, the two groups did not differ in a
statistically
significantly fashion in 2-hydroxylation, which was 5% higher in patients. The ratio of the
average level of 2-hydroxylation to the average level of 16
-hydroxylation was 52%
greater in the control subjects than in the patients with breast cancer. Adlercreutz et al. (4) examined estrogen metabolites in 10 young Finnish premenopausal
patients with breast cancer, 12 control women who were omnivorous, and 11 control women who
were lacto-vegetarians. There was no statistically significant difference in 2-OHE1 or
16
-OHE1 for these groups. In another study, Adlercreutz et al. (43) reported that the ratio of 2-hydroxylation products to 16
-hydroxylation
products was fourfold to fivefold higher among premenopausal Finnish women at high risk for
breast cancer than among 13 premenopausal Asian women, a low-risk population, contrary to the
hypothesized result (12-14).
Kabat et al. (17) obtained spot urine samples from 42 patients with
breast cancer and 64 women attending a free breast cancer screening clinic. They found no
differences in the ratio 2-OHE1/16OHE1 between these patients
and
control subjects. However, they reported a statistically significantly lower ratio in the 23 patients
than in the 28 control subjects who were postmenopausal. There was no weight restriction in that
study; thus, it is conceivable that the impressive results in postmenopausal women might have
been due to inclusion of obese postmenopausal patients with breast cancer, who, because of their
obesity, have abnormally low levels of 2-hydroxylation products (44).
Furthermore, the majority of the patients with breast cancer in this study had recently undergone
surgery. Compounds with a substantial hepatic metabolism may reduce 2-hydroxylation (23,45); the effect that barbiturates administered as part of general
anesthesia may have on 2-hydroxylation is unknown.
Recently, Meilahn et al. (18) conducted a nested case-control study
within the Guernsey III cohort follow-up. They reported a median for the ratio 2-OHE1/16-OHE1 of 1.6 for the 42 postmenopausal patients and of 1.7 for the
139 matched control subjects. Compared with the postmenopausal women who had values for
the
ratio 2-OHE1/16
-OHE1 in the lowest third, women who had values
in the highest third had an OR for breast cancer of 0.71, but the CI was wide and not statistically
significant (95% CI = 0.29-1.75).
Experimental studies lend some support to the hypothesis of a protective effect for a high
2-OHE1/16-OHE1 ratio. In vitro data suggest that
16
-OHE1 induces a higher rate of cell proliferation than 2-OHE1 (46,47) and that 16
-OHE1 induces tumors in hamsters (48). Furthermore, the extent of [3H]E2 metabolism via the 16
-hydroxylation pathway was reported to be 4.6-fold higher in
terminal duct lobular units in breast tissue from patients with breast cancer than in breast tissue
from control subjects who underwent reduction mammoplasty (49).
However, not all data are supportive. In fact, some investigators (50) found that 2-hydroxylated metabolites stimulate proliferation in MCF-7 cells. Furthermore, there is evidence that catechol estrogens can cause DNA damage directly by forming quinones and semiquinones and DNA damage indirectly through the production of radical intermediates during metabolic redox cycling between catechol and quinone forms (10).
Our results, although clearly not supportive of this hypothesis, may have been affected by several factors. We purposely studied a select group of women with few extraneous factors that might influence estrogen metabolism but excluded a large number of women. However, the exclusions were applied equally to patients and control subjects, and none of these exclusions appears likely to introduce any biases in one direction or the other.
Despite our many attempts to contact patients and control subjects, we cannot exclude the
possibility that women with a healthy lifestyle (and a high 2-OHE1/16-OHE1 ratio) may have been more likely to participate in this study than other women.
However, we would expect this to be more frequent among control subjects. If so, one would
expect any bias to favor the hypothesis of Bradlow et al. (12-14).
We studied patients with breast cancer who were diagnosed and had been treated for early
stage breast cancer 3-7 years earlier. It is not known whether the onset of cancer and its sequelae
may affect 2-hydroxylation and 16-hydroxylation. If so, then this would be a limitation in
any case-control test of the 2-OHE1/16
-OHE1 hypothesis that
collected urine samples after the disease process had started.
Certain medications, including tamoxifen, influence the hydroxylation pattern (22-25); therefore, we excluded all women who had ever been treated with chemotherapy or who had recently used tamoxifen. Because our study took place several years after breast cancer surgery, we think it is unlikely that the primary treatment for breast cancer affected the hydroxylation pattern among the patients.
Whether survival may be poorer in patients with breast cancer who have a lower 2-OHE1/16-OHE1 ratio is unknown. However, we only studied patients
with early stage disease for whom survival is high; only 4.1% had died.
The evidence is rather clear that certain diets influence the extent of 16-hydroxylation
and 2-hydroxylation (45,51-53). However, adjustments for usual intake
of macronutrients and recent intake of cruciferous vegetables or alcohol did not change the
results. Rather than using a 24-hour urine collection, we used a first morning void urine sample
and adjusted for creatinine. Other investigators (17) have used similar
approaches and have obtained positive results.
In contrast to most previous studies, our study was based on a population-based, case-control
study, not a convenience sample of patients and control subjects. It was able to demonstrate
effects as large as those observed by Kabat et al. (17) with very high
statistical power. However, our results from this case-control study of breast cancer in
postmenopausal women support no association between the ratio of urinary 2-OHE1
to 16-OHE1 and the risk of breast cancer.
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NOTES |
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Supported by grants DAMD17-94-J-4289 and DAMD17-94-J-4049 (G. Ursin from the U.S. Army Medical Research and Materiel Command; by Public Health Service grant P01CA17054 (G. Ursin) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; and by the California Department of Health Services, through the California Public Health Foundation, as part of its statewide cancer reporting program, mandated by Health and Safety Code Sections 210 and 211.3. G. Ursin and S. London were supported in part by Research Career Development Awards from the Stop Cancer Foundation.
The ideas and opinions expressed herein are those of the authors, and no endorsement by the State a California Department of Health Services or the California Public Health Foundation is intended or should be inferred.
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Manuscript received November 19, 1999; revised April 7, 1999; accepted April 15, 1999.
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