Risk of Endometrial Cancer Following Estrogen Replacement With and Without Progestins

Elisabete Weiderpass, Hans-Olov Adami, John A. Baron, Cecilia Magnusson, Reinhold Bergström, Anders Lindgren, Nestor Correia, Ingemar Persson

Affiliations of authors: E. Weiderpass, C. Magnusson, N. Correia, I. Persson, Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden; H.-O. Adami, Department of Medical Epidemiology, Karolinska Institutet, and Department of Epidemiology and Harvard Center for Cancer Prevention, Harvard University, Boston, MA; J. A. Baron, Dartmouth Medical School, Hanover, NH; R. Bergström, Department of Medical Epidemiology, Karolinska Institutet, and Department of Statistics, Uppsala University, Sweden; A. Lindgren, Department of Pathology, Falun Hospital, Sweden.

Correspondence to: Elisabete Weiderpass, M.D., M.Sc., Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden (e-mail: Elisabete.Weiderpass{at}mep.ki.se).


    ABSTRACT
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Notes
 References
 
BACKGROUND: Unopposed estrogen replacement therapy (i.e., estrogen without progestins) increases the risk of endometrial cancer. In this study, we examined the endometrial cancer risk associated with combined estrogen-progestin regimens currently in use, since the safety profiles of these regimens have not been clearly defined. METHODS: We conducted a nationwide population-based, case-control study in Sweden of postmenopausal women aged 50-74 years. We collected information on use of hormone replacement from 709 case patients with incident endometrial cancer and from 3368 control subjects. We used unconditional logistic regression to calculate odds ratios (ORs) as estimates of relative risks. All individual comparisons were made with women who never used the respective hormone replacement regimens. RESULTS: Treatment with estrogens alone was associated with a marked duration- and dose-dependent increase in the relative risk of endometrial cancer. Five or more years of treatment had an OR of 6.2 for estradiol (95% confidence interval [CI] = 3.1-12.6) and of 6.6 for conjugated estrogens (95% CI = 3.6-12.0). Following combined estrogen-progestin use, the association was considerably weaker than that for estrogen alone; the OR was 1.6 (95% CI = 1.1-2.4) after 5 or more years of use. This increase in risk was confined to women with cyclic use of progestins, i.e., fewer than 16 days per cycle (most commonly 10 days per cycle [OR = 2.9; 95% CI = 1.8-4.6 for 5 or more years of use]), whereas continuous progestin use along with estrogens was associated with a reduced risk (OR = 0.2; 95% CI = 0.1-0.8 for 5 or more years of use). CONCLUSION: The risk of developing endometrial cancer is increased after long-term use of estrogens without progestins and with cyclically added progestins. Continuously added progestins may be needed to minimize the endometrial cancer risk associated with estrogen replacement therapy.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Notes
 References
 
Although menopausal estrogen replacement therapy without progestins ("unopposed" estrogen replacement) is an established causal risk factor for endometrial cancer, important uncertainties remain regarding combined estrogen-progestin regimens (1,2). The addition of progestins is thought to counteract the estrogen-associated increase in risk, but epidemiologic data regarding combined treatments are inconclusive and are, in fact, frequently contradictory (3–8). Only two studies (3,4) have provided reasonably precise relative risk estimates, and only one (3) of these studies considered continuous combined regimens with daily addition of a progestin to the estrogens.

Important issues to be clarified include the safety of different combined regimens, i.e., the impact of number of days the progestins are added to estrogens, type of regimen, and dose of the added progestins (2). We report here the results of a large nationwide, population-based study in Sweden, designed to assess the impact of different hormone replacement regimens on endometrial cancer risk in a setting where estrogens with progestins have been widely used for many years.


    SUBJECTS AND METHODS
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Notes
 References
 
This population-based, case-control study was conducted among women aged 50-74 years, who were born and residing in Sweden during the period from January 1, 1994, through December 31, 1995. We restricted our study to postmenopausal women with an intact uterus and no previous diagnosis of endometrial or breast cancer. Eligible as case patients (n = 1055) were women with an incident, primary, histopathologically confirmed endometrial cancer. The case patients were identified through six regional cancer registries in Sweden, which comprise a virtually complete cancer registration system (9). Case women were approached after approval from their physicians.

Control women (n = 4216) were randomly selected from a continuously updated population register including all residents in Sweden. To coordinate use of resources, most of the control women (n = 2633) were also subjects in a concomitant breast cancer case-control study that used the same questionnaire (10); 735 control women were separately sampled after completion of the breast cancer study in March 1995 to ensure that the recruitment period for endometrial cancer case patients and the control women was identical. Thus, control women were frequency matched to the expected age distribution of either breast or endometrial cancer case patients.

Participation rates were 75% among the case patients (789 of 1055 eligible) and 79.9% among the control women (3368 of 4216 eligible). Nonparticipation was due to refusal in 171 (16.2%) of 1055 eligible case patients and in 811 (19.2%) of 4216 eligible control women and to death or poor health in 37 (0.88%) control women. The patients' physicians refused permission to contact an additional 95 (9%) case patients, mostly because of poor health of these patients. The study was approved by the local Ethics Committee.

Data Collection

Data and informed consent were obtained from the subjects through mailed questionnaires requesting detailed information on use of replacement hormones, including brand, dosage, date of first and last use of each treatment episode, and treatment indication. Recall was aided by a picture chart of all brands commercially available in Sweden during the years 1950 through 1995. The questionnaire also covered reproductive and medical histories, anthropometric measures, and life style (e.g., smoking, drinking, and dietary habits). Among case patients, the mean interval from diagnosis to questionnaire response was 8.4 months (standard deviation, 4.6 months).

Age at menopause was defined as the age at the last menstrual period or the age at bilateral oophorectomy, if 1 year or more prior to data collection. If later, women were considered to be premenopausal and were excluded.

Women with menses due to hormone replacement therapy or with missing information on age at menopause were considered to be postmenopausal if they had reached the 90th percentile of age at natural menopause of study subjects (current smokers: 55 years old for both case patients and control subjects; nonsmokers: 56 years old for case patients and 55 years old for control subjects). Subjects thus classified as postmenopausal (44 case patients and 206 control women) were assigned an age at menopause according to their current smoking status and the mean ages at natural menopause in our data (current smokers: 51 years old for case patients and 50 years old for control subjects; nonsmokers: 52 years old for case patients and 50 years old for control subjects). Women with missing information on age at menopause who had not reached the 90th percentile of age at natural menopause of the study subjects were excluded from the analyses (one case patient and 51 control subjects).

Among participating control subjects, 491 (14.6%) of 3368 failed to return the mailed questionnaire but agreed to a telephone interview that included most questionnaire items (except family history of cancer, profession, alcohol consumption, and medical history). Case patients were not approached by phone, since all who had consented returned the questionnaires. Approximately 50% of all case patients and 50% of control subjects were contacted by telephone for essential completion of missing information in their mailed questionnaires, mainly details of hormone use.

Histopathologic Classification

Histologic specimens from the case patients were retrieved from all 35 pathology departments in Sweden participating in the study. These specimens were reviewed by one of us (A. Lindgren), who was blinded to hormone use or to any other exposures of case patients and who reclassified the specimens as endometrioid adenocarcinoma (n = 648), seropapillary carcinoma (n = 36), clear cell carcinoma (n = 10), adenoacanthoma (n = 3), adenosquamous carcinoma (n = 12), or endometrial atypical hyperplasia (n = 80) (defined as adenomatous hyperplasia with slight, moderate, or severely pronounced atypia). Case patients with anaplastic carcinoma (n = 13), malignant mixed Mullerian tumors (n = 6), or cancer diagnoses other than endometrial (n = 4) and those whose histopathologic slides were missing (n = 5) were excluded from the study. Endometrioid adenocarcinomas (n = 648) were further classified as well differentiated (grade 1; n = 241 or 37.2%), moderately differentiated (grade 2; n = 286 or 44.1%), or poorly differentiated (grade 3; n = 121 or 18.7%). Endometrial cancers, in total 709, and 80 atypical hyperplasias were analyzed separately, and all analyses—except those in Table 7 —included only case patients with invasive cancer. Hysterectomy specimens were available from 542 (76.4%) of 709 case patients. Myometrial invasion was classified as none or less than 50% in 362 case patients (66.8% of those with slides available for myometrial histology), 50% or more of the myometrial thickness, or through the serosa in 180 case patients (33.2%).

Stratification on the Basis of Hormone Treatment

We classified each reported treatment episode into one of the four categories listed below (11). The potencies refer to the biologic effects of the compounds, and the doses refer to actual amounts given to women.

  1. Medium-potency estrogens (i.e., conjugated estrogen, estradiol, and other synthetic estrogens), without added progestins. Low and high doses, respectively, were defined as:

  2. Medium-potency estrogens (as described in category 1), cyclically combined with a progestin (<16 days per cycle, most commonly 10 days) or added continuously (>=19 days per cycle, most commonly 28 days with 1 mg of norethisterone acetate). No woman in this population used progestins (added to estrogens) for 16-18 days per cycle. We also considered combined treatment with 19-nortestosterone derivatives (e.g., norethisterone, norethisterone acetate, levonorgestrel or lynestrenol) or progesterone-like progestins (17-hydroxyprogesterone derivatives, e.g., medroxyprogesterone acetate).
  3. Low-potency estrogens: oral estriol (1-2 mg per day) or vaginal dienoestrol (0.1-0.5 mg), estriol (0.5-1 mg), or estradiol (25 µg). The usual prescription for vaginal use was daily applications during the initial 2-3 weeks of treatment followed by applications twice a week.
  4. Progestins without estrogen.

We censored all exposures after an index date: in case patients, 6 months before diagnosis; in control women, the date of the questionnaire arrival minus the mean time from diagnosis to questionnaire arrival time in case patients minus an additional 6 months.

Statistical Methods

As measures of relative risk, odds ratios (ORs) were computed from unconditional logistic regression models fit by the maximum likelihood method (12). All P values are two-sided. Trends in ORs were tested on the basis of models with the explanatory variable in continuous form. A substantial proportion of all women had used several different hormone regimens, and we employed two strategies to assess their independent effects. The first strategy used all subjects, adjusting for hormone replacement regimens other than the one under study in the modeling. The second strategy included women who had used only the studied compounds or no hormone replacement at all. Since the two approaches yielded very similar results, we present estimates obtained by the first strategy to preserve statistical power. We also repeated most analyses in two other ways: 1) excluding women with an assigned age at menopause and 2) excluding control women who responded only to the telephone interview. Results of these analyses were virtually identical to those presented and will not be shown.

Analyses of the association of endometrial cancer and hormone replacement were adjusted for the following covariates: age (as a continuous variable), smoking (ever or never smoked regularly), parity (nulliparous, one to three children, or four or more children), age at last birth (nulliparous, <27 years old, 27-29 years old, 30-33 years old, and >=34 years old), age at menopause (<45 years old, 45-49 years old, 50-51 years old, 52-54 years old, and >54 years old), body mass index (BMI [body weight in kg/height in m2], according to quartiles among control subjects), and use of oral contraceptives (never or ever).

We also considered the potential confounding effects of other covariates, i.e., education, history of diabetes mellitus and hypertension, family history of endometrial cancer, age at menarche, age at first birth, duration of breast-feeding, and use of vaginal low-potency estrogens. However, these covariates were not included in the final models because they did not substantially affect relative risk estimates or significantly improve goodness of fit (assessed through likelihood ratio tests) (13). Estimates of increment in relative risk per year of hormone use were calculated, including unexposed women. Interactions between exposures to estrogens alone or to progestins combined cyclically or continuously with estrogens were evaluated by including appropriate product terms in the models.


    RESULTS
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Notes
 References
 
The characteristics of the study participants are summarized in Table 1. The differences between case patients and control women regarding age at menopause, parity, use of oral contraceptives, and smoking reflected established epidemiologic associations.


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Table 1. Characteristics of participant postmenopausal endometrial cancer case patients and control subjects

 
Estrogens Without Progestins

Intake of estrogens without progestins, reported by 98 case subjects (14.3%) and 177 control women (5.4%) (Table 1), conferred a threefold increased relative risk of endometrial cancer. Relative risk increased by 17% per year of use (OR = 1.17; 95% confidence interval [CI] =1.12-1.21) to an OR of more than 8 after 10 years (Table 2). The excess relative risk persisted even 5 or more years after cessation of treatment when the OR for long-term users was 6.3 (95% CI = 3.4-11.8) (Table 2).


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Table 2. Odds ratio (ORs) and 95% confidence intervals (CIs) of invasive endometrial cancer in relation to use of medium-potency estrogens without progestins

 
Among the 275 (100%) women (98 case patients and 177 control subjects) who used estrogens without progestins, 94 (34.2%; 43 case patients and 51 control subjects) had used conjugated estrogens, 180 (65.4%; 55 case patients and 125 control subjects) had used estradiol, and 20 (7.3%; 11 case patients and nine control subjects) had used other synthetic compounds. Only 19 subjects (6.9%; 11 case patients and eight control subjects) reported use of more than one type of estrogen. Conjugated estrogens and estradiol carried similar patterns of risk. Five or more years of treatment entailed about a sixfold excess relative risk for both drugs (for conjugated estrogens, OR = 6.6 [95% CI = 3.6-12.0]; for estradiol, OR = 6.2 [95% CI = 3.1-12.6]) (Table 3), while 10 or more years of use were associated with ORs of 9.2 (95% CI = 4.4-19.4) and 7.5 (95% CI = 3.0-18.9), respectively.


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Table 3. Odds ratios (ORs) and 95% confidence intervals (CIs) of invasive endometrial cancer in relation to use of medium-potency estrogens without progestins, by type and dose of estrogen compound

 
The corresponding increments in relative risk per year of use were 15% (OR = 1.15; 95% CI = 1.10-1.20) for conjugated estrogens and 17% (OR = 1.17; 95% CI = 1.10-1.23) for estradiol (Table 3).

Relative risk for endometrial cancer was strongly related to the daily dose of estrogens. After 5 or more years of use, women prescribed low-dose regimens had a fourfold increased relative risk, and women prescribed higher doses had an eightfold increase. The corresponding increments in relative risk per year of use were 12% (OR = 1.12; 95% CI = 1.04-1.20) and 18% (OR = 1.18; 95% CI = 1.13-1.24), respectively (Table 3).

Estrogens With Progestins

Intake of estrogens with progestins was reported by 119 case subjects (17.2%) and by 477 control women (14.6%) (Table 1) and conferred an overall 30% increased relative risk of endometrial cancer (Table 4). However, the excess relative risk was statistically significant only after 10 or more years of use. The estimated increment in relative risk per year of use was 6% (OR = 1.06; 95% CI = 1.02-1.10) (Table 4). In contrast to the findings reported for unopposed estrogen use, no substantial elevation of the relative risk remained 5 or more years after cessation of use (Table 4).


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Table 4. Odds ratios (ORs) and 95% confidence intervals (CIs) of invasive endometrial cancer in relation to use of medium-potency estrogens with progestins

 
Among the 596 (100%) women (119 case patients and 477 control subjects) who used estrogens with progestins, 390 (65.4%; 90 case patients and 300 control subjects) had used cyclic progestins with estrogens, 278 (46.6%; 41 case patients and 237 control subjects) had used continuous estrogen-progestin, and 72 (12%; 12 case patients and 60 control subjects) had used a mixture of both regimens. Among the 390 users of a cyclic regimen, 17 (4.4%) received progestins for fewer than 10 days of the cycle and 368 (94.3%) received them for 10-14 days (315 or 81% of subjects received treatment for 10 days), whereas five (1.3%) subjects reported receiving a mixture ranging from 5 to 14 days. Thus, our analyses of cyclic regimens pertained largely to women who used progestin for 10 days per cycle. Among the 278 women who reported receiving continuous combined regimens, 276 (>99%) had daily progestins and two (<1%) had progestins 21 days per cycle.

The increase in relative risk for endometrial cancer associated with combined regimens was confined to women exposed to cyclic addition of progestins, whereas continuous addition of progestins actually reduced the relative risk (Table 5) (P for trend over categories of duration of use = .02). ORs per year of use were 1.10 (95% CI = 1.06-1.15) for cyclic regimens and 0.86 (95% CI = 0.77-0.97) for continuous combined treatment.


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Table 5. Odds ratios (ORs) and 95% confidence intervals (CIs) of invasive endometrial cancer in relation to use of medium-potency estrogens with progestins, by type of addition of progestin and progestin derivation

 
There was no evidence of an interaction between use of estrogens without progestins or with progestins added cyclically or continuously, since the differences in the OR in logistic regression models including or excluding the interaction terms were not statistically significant (two-sided P = .69, likelihood ratio test for interaction).

We also analyzed subgroups of progestins classified according to their derivation. Among the 596 (100%) women (119 case patients and 477 control subjects) who used estrogens with progestins, 30% (177 women in total, or 51 case patients and 126 control subjects) used combinations with a progesterone-derived progestin, 81% (483 women in total, or 85 case patients and 398 control subjects) used a 19-nortestosterone-derived progestin, and 11% (64 women; 17 case patients and 47 control subjects) used both types. Regimens with progesterone-derived progestins were associated with an increase in relative risk for endometrial cancer (OR per year of use = 1.12; 95% CI = 1.06-1.18), whereas no association was found with testosterone-derived progestins (OR per year of use = 1.00; 95% CI = 0.95-1.06) (Table 5).

We used further stratified analyses to separate the effects of pattern of use and progestin derivation (Table 6). Progesterone-derived progestins seemed to lead to higher relative risks of endometrial cancer than did testosterone-derived progestins, regardless of the type of regimen. Continuous addition of testosterone-derived progestins entailed statistically significant protection. The number of women who used continuous regimen with progesterone-derived progestins was small for the analysis (Table 6).


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Table 6. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) showing the estimated increment in risk for endometrial cancer per year of use among women using estrogens with progestins, by regimen and chemical derivation of the progestin*

 
Tumor Grade and Invasiveness

Analyses of the association of hormone replacement with tumors having different histopathologic characteristics were hampered by the small numbers. However, some interesting patterns emerged. The ORs for use of estrogens without progestins became increasingly elevated with increasing differentiation of the endometrial neoplasia (Table 7). Following 5 or more years of use, relative risks increased about ninefold for atypical hyperplasias and well-differentiated tumors, fivefold for moderately differentiated tumors, and fourfold for poorly differentiated tumors (data not shown). The excess relative risk following replacement with estrogens without progestin was slightly higher for tumors with no or limited myometrial infiltration than for tumors with 50% or more infiltration. Among users of combined regimens, a similar pattern appeared, but it was confined to cyclic treatment (Table 7).


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Table 7. Multivariate* odds ratios (ORs) and 95% confidence intervals (CIs) showing the estimated increment in risk for endometrial cancer per year of use of different hormone replacement regimens, by histologic grade and degree of invasion of the myometrium

 

    DISCUSSION
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Notes
 References
 
In this large, population-based, case-control study, we found convincing evidence that treatment with conjugated estrogens or estradiol without progestins confers a marked and rather persistent duration- and dose-dependent increase in relative risk for endometrial cancer. The increased relative risk was slightly more marked for atypical hyperplasias and well-differentiated and moderately differentiated tumors. Combination regimens with added progestins for fewer than 16 days also conferred an increased relative risk, although much less pronounced than for estrogens alone. Addition of progestins throughout the complete cycle appeared to reduce the relative risk below the levels seen in unexposed women.

The strengths of our study include the population-based design, the detailed information on hormone regimens, and the uniform histopathologic classification. Although data collection through telephone interviews in 15% of control subjects could have introduced information bias, the likely enhancement of exposure recall in these control subjects would probably have led to an underestimation of relative risks. Concern about recall bias is offset, at least in part, by clear patterns of relative risk with types of hormones used and with histopathologic features of the tumor. Heightened surveillance among women receiving estrogens is likely, since estrogens are well known to enhance risk for endometrial cancer. However, in the Swedish health care system with readily available service for all citizens, postmenopausal vaginal bleeding would lead to an endometrial biopsy with short delay, regardless of such exposure.

An association between use of estrogens without progestins and risk of endometrial cancer has been consistently found (14). Less well known is the persistence of the effect even after 5 years of cessation. This pattern clearly emerged in our data and can also be discerned in some prior reports (15,16). Our findings regarding cyclically added progestins, mainly for 10 days of each cycle, agree with those recently published (4), showing that 5 years or more of cyclic use yielded a threefold excess risk. In contrast, a smaller study (3) found no increase in risk for cyclic regimens with 10 or more days of progestin per cycle. As for treatment with estrogens alone, the excess risk seemed to persist beyond 5 years of cessation.

The only published data regarding continuously combined treatment suggested an absence of an association with endometrial cancer (3), in contrast to the significantly reduced risk that we observed. The predominant regimen used by our subjects—estradiol (2 mg) plus norethisterone acetate (1 mg)—may have more potent progesterone-like effects than the compounds studied by Pike et al. (3), i.e., conjugated estrogens and medroxyprogesterone acetate (17). Although never previously documented, a protective effect of continuous, combined regimens is plausible, since combined oral contraceptives—providing a continuous combination of synthetic and high-dose estrogens and progestins—clearly reduce endometrial cancer risk in premenopausal women (14).

A gradient in the effects of estrogens without progestins on risk according to tumor grade has been previously reported (1,7,18), and we now extend those observations to tumors after combined estrogen-progestin treatment. Considered together, these results suggest that exogenous hormones predominantly cause less aggressive tumors. Higher risks for conjugated estrogens than for synthetic estrogens (1) were, however, not confirmed in our data.

Estrogenic stimulation promotes endometrial proliferation and can eventually cause hyperplasia, atypia, and neoplasia (19). Added progestins counteract estrogenic effects through several mechanisms, including reduction in the estrogen receptor levels, enhancement of estradiol metabolism by estradiol-17ß dehydrogenase, regulation of several growth factors, decreased DNA synthesis, and endometrial shedding (19-23).

Our finding that addition of progesterone-derived progestins seemed to confer a somewhat higher endometrial cancer risk than addition of testosterone-derived progestins is based on a small number of exposed subjects and clearly needs confirmation. Separate effects might be due to differences in hormonal mechanisms or to variation in the progestin potency of the two types of compounds or to both. In one previous study (24), 1 mg of norethisterone produced a similar endometrial secretory response as 125 µg of levonorgestrel or 11 mg of medroxyprogesterone acetate when given for 7 days in women using conjugated estrogens. Among women in our study who used cyclic regimens (Table 6), the predominant doses of testosterone-derived compounds were 1 mg for norethisterone acetate (17.0%) and 250 µg for levonorgestrel (48.0%), whereas doses of medroxyprogesterone acetate were on the average less than 10 mg (66.0% with intake of 5 mg). Thus, the testosterone-derived progestins were prescribed in relatively higher doses than the progesterone-derived compounds, possibly explaining in part our observation of differential effects on endometrial cancer risk.

Hormone replacement is becoming increasingly common in many countries, both for alleviation of menopausal symptoms and for prevention of osteoporosis and cardiovascular diseases. Continuous addition of a progestin appears to be the safest regimen for women with a uterus, but a more complete evaluation of the risk-benefit balance is complex. There is no clear evidence that adding progestins throughout the cycle rather than say 10 days or not at all would be more harmful to the breast and cardiovascular system. These issues are incompletely studied, however, and deserve further investigation.


    NOTES
 
Supported by research grant (EDT-89) from the American Cancer Society; by Public Health Service grant R01CA58427 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; and by grants from the Swedish Cancer Society.

We thank Dr. Thomas Riman for his supervision of the field work.


    REFERENCES
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Notes
 References
 

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Manuscript received December 9, 1998; revised May 3, 1999; accepted May 7, 1999.


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