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American Journal of Epidemiology Advance Access originally published online on September 22, 2006
American Journal of Epidemiology 2006 164(8):775-786; doi:10.1093/aje/kwj316
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American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

Original Contribution

Case-Control Study of Postmenopausal Hormone Replacement Therapy and Endometrial Cancer

Brian L. Strom1,2,3,4,5, Rita Schinnar3, Anita L. Weber3, Greta Bunin3,5,6, Jesse A. Berlin7, Mona Baumgarten8, Angela DeMichele1,2,3,5, Stephen C. Rubin5,9, Michelle Berlin10, Andrea B. Troxel2,3,5 and Timothy R. Rebbeck2,3,5

1 Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA
2 Department of Biostatistics and Epidemiology, School of Medicine, University of Pennsylvania, Philadelphia, PA
3 Center for Clinical Epidemiology and Biostatistics, School of Medicine, University of Pennsylvania, Philadelphia, PA
4 Center for Education and Research in Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA
5 The Abramson Cancer Center, Children's Hospital of Philadelphia, Philadelphia, PA
6 Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
7 Pharmaceutical Research and Development, Johnson & Johnson, Titusville, NJ
8 Department of Epidemiology and Preventive Medicine, School of Medicine, University of Maryland, Baltimore, MD
9 Department of Obstetrics and Gynecology, School of Medicine, University of Pennsylvania, Philadelphia, PA
10 Center for Women's Health and Departments of Obstetrics and Gynecology, Public Health, and Preventive Medicine, Oregon Health and Science University, Portland, OR

Correspondence to Dr. Brian L. Strom, Center for Clinical Epidemiology and Biostatistics, School of Medicine, University of Pennsylvania, 824 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021 (e-mail: bstrom{at}cceb.med.upenn.edu).

Received for publication September 14, 2005. Accepted for publication March 20, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
This study evaluated recent inconsistent findings that adding progestins to postmenopausal estrogen replacement therapy protects against endometrial cancer. Using a population-based case-control study, the authors compared 511 endometrial cancer cases aged 50–79 years in the Philadelphia, Pennsylvania, region during 1999–2002 with 1,412 random-digit-dialing controls regarding postmenopausal hormone replacement therapy (HRT) use. Telephone interviews were performed with memory aids mailed in advance. An increased risk of endometrial cancer was observed among postmenopausal women using only unopposed estrogen for 3 or more years, compared with women who never used HRT (adjusted odds ratio = 3.4, 95% confidence interval (CI): 1.4, 8.3). Using combination HRT (of any duration) was associated with a substantial reduction in risk (odds ratio = 0.8, 95% CI: 0.6, 1.1). Comparing women using only combined estrogen and progestin for 3 or more years with women using only unopposed estrogen for 3 or more years, the authors found that the adjusted odds ratio was 0.2 (95% CI: 0.1, 0.6). Long-term use of unopposed estrogen is associated with increased risk for endometrial cancer, whereas combined estrogen plus progestin hormone therapy is not. Thus, if HRT is to be used in women with an intact uterus, this study confirms the benefit of adding progestins to the regimen.

case-control studies; endometrial neoplasms; estrogens; hormone replacement therapy; progestins

Abbreviations: CHRT, combination estrogen and progestin; CI, confidence interval; ERT, estrogen replacement therapy; HRT, hormone replacement therapy; OR, odds ratio


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
With cessation of ovarian function, postmenopausal women become estrogen deficient and susceptible to estrogen withdrawal. Because of the protective effect of postmenopausal estrogen replacement therapy (ERT) against osteoporosis (1Go) and the efficacy of ERT for common estrogen withdrawal symptoms, including vasomotor symptoms, atrophic vaginitis, and sleep disorders (2Go–4Go), ERT use soared in the United States and Canada between 1960 and 1975.

Parallel with this rise, reports appeared of increasing incidence of endometrial cancer (5Go–9Go) and hysterectomy (10Go). Several observational studies showed high relative risks for endometrial cancer following unopposed estrogen use, even for short duration (11Go). In response, estrogens were supplemented with progestins. One randomized trial of estrogen/progestin combination drugs found a significantly reduced incidence of adenomatous and atypical hyperplasia when progestin was taken for 10 or more days monthly (12Go). Another trial found an incidence of abnormal biopsy results in women receiving estrogen/progestin combination drugs comparable to that in women receiving placebo (13Go). These results suggested that combination hormone replacement therapy (HRT) protected the endometrium from the hyperplastic changes associated with estrogen-only therapy (13Go). Ensuing studies reported a decrease in endometrial cancer incidence (14Go, 15Go), attributed to the increasing use of HRT comprising both estrogens and progestins (16Go–19Go).

However, subsequent results have been contradictory (11Go). Some studies found combination therapy to be more or less protective according to how the combination therapy was used. For example, a protective effect was documented for continuous (20Go) or sequential use for at least 14 days per month but not for sequential use of fewer than 10 days per month (21Go), although both sequential regimens appeared to increase the risk for women using these drugs for 5 or more years (21Go). Many studies did not properly control for confounding or were underpowered and, thereby, inconclusive. A meta-analysis (11Go) highlighted the uncertainty of the conclusions regarding the potential benefit of combination therapy for endometrial cancer by reporting pooled results from case-control studies showing a statistically significant increased risk from combination estrogen and progestin therapy versus no HRT (odds ratio (OR) = 1.8, 95 percent confidence interval (CI): 1.1, 3.1), whereas pooled results from cohort studies showed a statistically significant decreased risk (OR = 0.4, 95 percent CI: 0.2, 0.6).

Even without definitive data on the effects of postmenopausal progestins, clinicians were prescribing these drugs widely (22Go–25Go). Combined HRT use was based on the assumption that progestins protected against the most serious known adverse effect of these drugs, that is, endometrial cancer, before it was definitively known whether progestins reduced the adverse effects of unopposed estrogens.

More recently, published findings from two large randomized controlled trials—the Heart and Estrogen/progestin Replacement Study (HERS) with 2,763 women recruited in 1993–1994 and the Women's Health Initiative (WHI) study with 16,608 women recruited in 1993–1998—showed that combined HRT was associated with no increased risk of endometrial cancer (26Go, 27Go), albeit again with modest statistical power, with overall relative risk = 0.4 (95 percent CI: 0.1, 2.0) and 0.8 (95 percent CI: 0.5, 1.5), respectively, especially for long-term users.

To complete our understanding of the risks of HRT use, we evaluated whether progestins have the intended effect of reducing the adverse effects of unopposed estrogens on the endometrium in a large population-based case-control study.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
The methods for this study have been described elsewhere (28Go). Potentially eligible cases were Black women or White women (including Hispanic women self-identifying as Black or White) aged 50–79 years, who were residents in the contiguous nine-county Philadelphia, Pennsylvania, region at the time of diagnosis and newly diagnosed with endometrial cancer between July 1, 1999, and June 30, 2002. Cases were identified through active surveillance at 61 of 68 hospitals in these counties. (Six hospitals closed as we were securing institutional review board approval, and one small hospital had no active institutional review board.) Case identification methods involved the medical records department and tumor registry in some sites or the pathology, laboratory, or surgery departments in other sites. Quarterly reviews of the Pennsylvania Cancer Registry lists were used to validate the completeness of case ascertainment.

Pathology reports and medical records were abstracted to validate diagnoses and to obtain information about tumor type, size, grade, degree of metastasis, and lymph node involvement. All reviews were performed, without knowledge of exposure status, by one of the coauthors (S. C. R.), a gynecologic oncologist. Endometrial cancer eligibility was considered validated by a pathology report compatible with primary, invasive, epithelial endometrial adenocarcinoma, of all stages and grades. Women were excluded if they had endometrial hyperplasia only, benign uterine lesions, lesions metastatic to the uterus, carcinoma in situ of the cervix, endolymphatic stromal myosis, mixed mesodermal mixed mullerian tumor, leiomyosarcoma, carcinosarcoma, undifferentiated carcinoma, and squamous cell carcinoma.

Random-digit-dialing controls were selected from the same geographic region as the cases, frequency matched to the cases on age (in 5-year age groups) and race (Black or White). Controls were selected by a survey research firm using a strict single-stage method in which every residential telephone number had an equal and known probability of selection.

Controls could not have a history of endometrial cancer or hysterectomy. Additional eligibility criteria for cases and controls included living in a noninstitutional setting; having a household telephone and the ability to speak English; and having no severe cognitive, language, or speech impairment. To minimize potential bias related to selecting controls from among individuals frequently at home, we required up to nine contact attempts at multiple times of the day and days of the week.

An introductory letter explaining the study was mailed to potentially eligible subjects. A few days later, they were phoned for a brief screening interview to determine eligibility and to schedule an interview. A package containing interview-related memory prompts (color photos of estrogen and progestin drugs, lists of the names of hormone drugs and other drugs, and a list of typical indications for HRT) and other study materials was mailed to each eligible woman before the telephone interview.

Women in the case group were excluded if the interval between diagnosis and case ascertainment exceeded 18 months, or if the interval between ascertainment and contact for the screening interview exceeded 12 months. Controls were interviewed within 12 months from the date of the random-digit-dialing screening interview.

Data collection
Telephone interviews, which averaged 60 minutes, were administered by trained lay interviewers with no knowledge of the study hypotheses. Although the interviewers could surmise that we wanted to know whether any of the listed medications increased risk, they did not know which medications were of interest, because we asked about hormone use as well as numerous other medications, herbs, and other natural medications. They also did not know for each whether the hypothesized association was causative or protective. For hormones and all other medications, we used similar hand cards; these were included in the mailed packet sent to participants and cited by interviewers during the interview. Also, given the breadth of topics covered by the interview (family history, fertility history, pregnancy history, menstrual and menopausal history, medical history, oral contraceptive history, hormone use, and medications history), the interviewers were unlikely to have guessed the study hypotheses.

Subjects were asked to refer to the photos and lists in the course of the telephone interview (29Go). For each hormone that a woman reported using, the questionnaire asked about the start and end dates of use; administration form (i.e., pill, shot, skin patch, vaginal cream, or suppository form); whether an estrogen and a progestin were used together (i.e., taken as combination drugs); whether the combination drugs were used continuously (daily or >24 days per month of progestin) or sequentially (daily estrogen and 5–14 days per month of progestin); and the weekly or monthly frequency that the hormone was used. Dose information was not collected.

Additional information sought by the interview included demographic characteristics; family history of breast, endometrial, and ovarian cancers in daughters, sisters, and mother; detailed contraceptive history, fertility history (including medications used to facilitate pregnancy), and pregnancy outcomes; menstrual and menopausal history; medical history; detailed gynecologic history; and use of medications, including herbal preparations commonly used for menopausal symptoms. All information on exposures pertained to a patient's history before the reference date, which was defined as the date of diagnosis for cases and the date of completion of the random-digit-dialing screening for controls.

Definition of study variables
Use of only unopposed estrogen (only ERT) was defined as exposure to ERT with no exposure to combination HRT or unopposed progestin. Use of any ERT was defined as exposure to ERT with some combination HRT or unopposed progestin. Use of only combination estrogen and progestin (only CHRT) was defined as exposure to CHRT and no history of exposure to unopposed estrogen or unopposed progestin. Use of any CHRT was defined as exposure to CHRT regardless of whether there were other periods of unopposed estrogen or unopposed progestin use. Further, we defined standard sequential HRT use as estrogen combined with 5–14 days monthly of progestin use; nonstandard sequential HRT use as estrogen combined with 15–24 days monthly of progestin use; and continuous combined HRT use as estrogen combined with 25–31 days monthly of progestin use. Finally, only use of pill or patch HRT was included in the definition of exposure. The few women using HRT injections, creams or gels, and vaginal suppositories were excluded from analysis. HRT use was defined as any use greater than 1 month.

Our definition of menopause was similar to that of the Women's Contraceptive and Reproductive Experiences Study (30Go), with two modifications. Our age cutoff was 50, not 55, years to maximize the number of eligible women in the primary analysis. A sensitivity analysis using age 55 years as the cutoff for postmenopausal status in women with unknown age at menopause was performed to explore the possibility that premenopausal women at 50–54 years were included among those we assumed were naturally menopausal; only about 20 percent of the women with known premenopausal status were aged 55 or more years. Moreover, to account for the possibility that HRT use might obscure the onset of natural menopause, the Women's Contraceptive and Reproductive Experiences Study required no HRT use during the 12 months preceding the last menstrual period, whereas we required no HRT at any time before the last menstrual period. All analyses were restricted to postmenopausal cases and controls and postmenopausal HRT use.

Statistical analysis
Odds ratios and 95 percent confidence intervals (31Go) were calculated for four targeted comparisons: unopposed estrogen use versus never use of HRT; combined estrogen and progestin use versus never use of HRT; combined estrogen and progestin use versus unopposed estrogen use; and use of continuous combination versus sequential combination. Odds ratios and 95 percent confidence intervals were calculated also for long duration (defined a priori as ≥3 years) of HRT use versus never use of HRT. Duration was also modeled as a continuous variable (excluding nonusers), and we tested the quadratic (nonlinear) component of this relation. Multiple conditional logistic regression (31Go) was performed to adjust simultaneously for matching variables (defined by combinations of age group and race) and known risk factors for endometrial cancer. A potential confounder was included in logistic regression models if it changed one or more of the target HRT odds ratios by 10 percent or more when added to the unadjusted model of case-control status and HRT (i.e., if the ratio of the unadjusted to the adjusted HRT odds ratio was >1.1 or <0.9) (32Go, 33Go). Confounders meeting this criterion included the following: 1) educational level; 2) body mass index during the age decade of the 40s (as a continuous variable); 3) number of full-term pregnancies (never pregnant, one full-term pregnancy, two full-term pregnancies, three or more full-term pregnancies, all other pregnancies); 4) years of menses (imputed if missing, as a continuous variable); 5) menopause type (natural, assumed natural but masked by hormone use, induced); 6) smoking (never, former, or current smoker); 7) years of smoking among former smokers; 8) years of smoking among current smokers; and 9) oral contraceptive use (never, <3 years, ≥3 years). Additional unconditional models, adjusted for age and the factors above, were fit to confirm the results obtained with the conditional models.

All analyses were performed with STATA, version 8.0, software (STATA Corporation, College Station, Texas). The study was approved by the University of Pennsylvania Committee on Studies Involving Human Beings and the institutional review boards of the 61 participating hospitals.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
We identified 1,185 incident cases with endometrial cancer meeting study criteria. Our case ascertainment procedures effectively identified most potentially eligible cases, as determined by comparing our cases with those in the Pennsylvania Tumor Registry. During an 8-month period for which the lists were compared, out of 128 cases identified in the Pennsylvania Tumor Registry, our study missed 11 cases in hospitals where ascertainment was limited by institutional review board restrictions and only three cases in hospitals where we benefited from open ascertainment procedures (yielding 89 percent successful ascertainment). During the same period, our study identified an additional 85 cases not included in the Tumor Registry, presumably because of late or deficient reporting by participating hospitals.

Of the 1,185 ascertained cases, 386 were excluded from further study for the following reasons: seven cases were living in a nursing home; 29 cases did not speak English; 17 cases were not mentally or physically able to participate; 194 cases did not have physician consent; 70 cases were without correct address and/or phone number; and 69 cases died before we could arrange interviews. Of the 799 remaining cases, another 153 cases (19 percent) refused, and 30 cases could not be interviewed before the study ended, leaving 616 cases interviewed (52 percent of ascertained cases, 77 percent of eligible and accessible cases). The 37 interviewed cases with clear cell and papillary serous cancers were excluded from analysis because these tumors are thought to develop through different pathways than tumors of other types (34Go). The 579 interviewed cases with eligible information on histology constitute the final sample for this analysis. We assessed the comparability of the interviewed and noninterviewed cases with respect to race and age; the noninterviewed cases were modestly older (36 percent of noninterviewed cases were aged 70 or more years vs. 23 percent of interviewed cases; p < 0.0001). We could not conduct a formal test for race differences, since nearly half (45 percent) of the noninterviewed cases were missing information on race.

The survey research firm provided the names, addresses, and telephone numbers for 2,708 potential random-digit-dialing controls. Of these, 405 were ineligible because of age, gender, county, race, or history of hysterectomy or endometrial cancer. Of the remaining 2,303 eligible controls, 25 could not participate because of physical or mental impairments; 12 did not speak English; seven were deceased; 207 could not be recontacted because they moved or changed their phone number; and 469 refused (17.3 percent of referred controls and 20.4 percent of eligible controls). The remaining 1,583 controls completed the interview (58 percent of referred controls, 77 percent of eligible and accessible controls). We assessed the comparability of the interviewed and noninterviewed controls with respect to county of residence and found significant differences (p < 0.0001). The noninterviewed controls were more likely to reside in Philadelphia County (51 percent of noninterviewed vs. 38 percent of interviewed), and the interviewed controls were more likely to reside in suburban counties. To the extent that cases and their matched controls were ascertained from identical counties, however, random-digit-dialing use ensured that cases and controls came from the same underlying study base.

The final analysis for this report was restricted to 511 postmenopausal endometrial cancer cases and 1,412 postmenopausal age group- and race-matched controls. Sixty-eight premenopausal cases and 171 premenopausal controls were excluded.

Endometrial cancer cases were older than were controls (for those aged 60 or more years, cases: 67.9 percent; controls: 57.2 percent) despite matching on age group (table 1). A higher proportion of cases were White, never married, and Jewish. The cases tended to have fewer years of schooling than the controls (53.6 percent vs. 46.0 percent without schooling beyond high school) and lower income (50.8 percent vs. 46.5 percent earning $45,000 or less).


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  		TABLE 1. Demographic characteristics of postmenopausal endometrial cancer cases and matched random-digit-dialing controls in the Philadelphia, Pennsylvania, area, 1999–2002

 
Cases exhibited many of the known risk factors for endometrial cancer (table 2). Diabetes, gallbladder and gallstone problems, and obesity (defined as a body mass index of ≥30 based on usual weight when the woman was aged ≥40 years) were significantly more frequent among endometrial cancer cases than among controls. Other known risk factors more common among cases included hypertension, younger age at menarche, older age at menopause, nulliparity, personal history of breast cancer, personal history of nonbreast and nonovarian cancers, and family history of endometrial cancer. Use of combined oral contraceptives, past or current history of cigarette smoking, osteoporosis, tubal ligation, younger age at first pregnancy, older age at last pregnancy, higher number of pregnancies, breastfeeding, and alcohol drinking were more common in controls than in cases. High cholesterol prevalence was not significantly different in cases and controls. Other variables showing no significant differences between cases and controls included birth weight; irregular menstrual periods; and history of polycystic ovaries, benign ovarian tumors, myocardial infarction, stroke, pulmonary embolism, liver disease, migraine headaches, and use of medications to treat heart arrhythmia, ulcers, tuberculosis, and seizures.


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  		TABLE 2. Risk factors for endometrial cancer among cases and random-digit-dialing controls in the Philadelphia, Pennsylvania, region, 1999–2002

 
The frequency of HRT use by postmenopausal women in our study was 44.5 percent (216/511 = 42.3 percent of cases and 640/1,412 = 45.3 percent of controls). HRT use among Black women was much lower than among Whites. Of the 393 Black women in the study, 10.4 percent had used any ERT of any duration, and 14.5 percent had used any combination HRT of any duration. Of the 1,530 White women, 14.1 percent had used any ERT of any duration, and 28.7 percent had used any combination HRT of any duration.

When compared with never users of any HRT, women using unopposed estrogen only for 3 or more years had almost double the risk of developing endometrial cancer (OR = 1.9, 95 percent CI: 0.8, 4.5, adjusted only for age group and race) (table 3). With adjustment for body mass index and other confounders, the odds ratio was higher and statistically significant (adjusted OR = 3.4, 95 percent CI: 1.4, 8.3). A reduction in this increased risk was apparent with CHRT use only (of any duration) (adjusted OR = 0.8, 95 percent CI: 0.6, 1.1). CHRT use for 3 or more years was similar to CHRT use of any duration. Comparing users of CHRT only for 3 or more years with users of unopposed estrogen only for 3 or more years showed a significant protective effect of CHRT (adjusted OR = 0.2, 95 percent CI: 0.1, 0.6). Analyses in which duration of HRT utilization was treated as a continuous variable revealed that the odds of endometrial cancer increased by 11 percent with every year of use of unopposed estrogen only (adjusted OR = 1.1, 95 percent CI: 1.02, 1.2). Conversely, duration of CHRT therapy only was not associated with a change in endometrial cancer odds (adjusted OR per year of use = 1.02, 95 percent CI: 0.97, 1.1). In addition, the test of the quadratic term for continuous duration was not significant for either ERT (p = 0.96) or CHRT (p = 0.84).


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  		TABLE 3. Hormone replacement therapy utilization among endometrial cancer cases and random-digit-dialing controls in the Philadelphia, Pennsylvania, region, 1999–2002

 
Use of only continuous CHRT (vs. nonuse of any HRT) (adjusted OR = 0.7, 95 percent CI: 0.5, 1.0) was protective, compared with use of only standard sequential CHRT (vs. nonuse of any HRT), which showed only a small, nonsignificant reduction in risk (adjusted OR = 0.9, 95 percent CI: 0.4, 2.0). Direct comparison of only continuous CHRT use with only sequential CHRT use again showed the more favorable effect of the former, although the association was not statistically significant (adjusted OR = 0.8, 95 percent CI: 0.3, 1.8). Because there were few nonstandard sequential combination users (i.e., estrogen combined with 15–24 days of monthly progestin use), this variable was not analyzed.

Further investigation of the models showed statistically significant effect modification of the ERT effect by body mass index, categorized into three groups (<21.5, 21.5–28.5, >28.5), such that the risk of any ERT use was greatest in those with lower body mass index (p = 0.02).

The results from sensitivity analysis using age 55 years as the cutoff for menopausal status in women with unknown age at menopause did not change the conclusions. Further, the unconditional models, adjusted for the confounders described above, as well as for age and race categories, resulted in nearly identical estimates for all odds ratios.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Our results are consistent with those of prior studies that showed an increased risk for endometrial cancer associated with long-term use of unopposed estrogen, which was not present with use of combined estrogen plus progestin hormone therapy of any duration.

On the basis of a case-control study in Sweden, Weiderpass et al. (35Go) reported an increased risk for women using combined estrogen-progestin for 5 or more years (OR = 1.6, 95 percent CI: 1.1, 2.4) but determined that this increased risk was limited to women with cyclic use of progestins (fewer than 16 days per cycle) (OR = 2.9, 95 percent CI: 1.8, 4.6), whereas continuous progestin use with estrogens was associated with a substantially reduced risk (OR = 0.2, 95 percent CI: 0.1, 0.8). Another recent case-control study (36Go) showed a nonsignificant protective effect from ever using combined HRT (OR = 0.9, 95 percent CI: 0.7, 1.2) of any duration and more pronounced protection when using the continuous combined HRT (OR = 0.5, 95 percent CI: 0.3, 0.8). A Japanese case-control study (37Go) similarly showed a protective effect for users of combined estrogen with progestin for 12 or more months, but the confidence interval was very wide (OR = 0.4, 95 percent CI: 0.1, 2.1). The results from clinical trials (27Go, 38Go) demonstrated the same, though neither was statistically significant. Finally, the recently published results from the Million Women Study of a cohort in the United Kingdom (39Go) showed a lower risk of endometrial cancer in women who reported last using continuous combined HRT (relative risk = 0.7, 95 percent CI: 0.6, 0.9). Our study further documents a statistically significant protective effect for both overall use of combination HRT for 3 or more years and continuous progestin use with estrogens. These findings from multiple studies with different designs are reassuring as to the risk of developing endometrial cancer after using combined estrogen with progestin therapy in menopause.

As in other studies, our study found reduced risk when a continuous combined estrogen/progestin replacement was used. Unlike most other studies, however, we did not observe an elevated risk with sequential combined therapy. We conclude that exposure to progestin hormone therapy (regardless of duration) provides protection against estrogen-induced endometrial cancer.

Finally, the significant interaction between body mass index and HRT, showing the greatest risk of estrogen use in women with lower body mass index, is likely explained by the lack of estrogen-producing fat tissue in these women, such that the additional estrogen effect from estrogen use is discernible. This observation helps to support the argument of biologic plausibility of the unopposed estrogen mechanism.

Several limitations may have influenced the results observed. Selection bias cannot be completely excluded because, although we successfully ascertained most of the endometrial cancer cases diagnosed during the study period, ultimately only 52 percent of cases were included in the study. Physicians refused to grant permission to contact 16 percent of the patients, and 13 percent declined participation in the study. Similarly, the participation rate for community controls identified through random digit dialing was only 58 percent. Lack of participation would only be a source of selection bias, however, if individuals who participated in the study differed in the prevalence of a risk factor from those who did not participate, a possibility that cannot be excluded. We did find some differences between participating and nonparticipating cases with respect to age and between participating and nonparticipating controls with respect to county of residence. However, these were controlled for as potential confounding variables.

Detection bias is a form of selection bias in which patients are selectively diagnosed with the disease of interest in a fashion relating to the exposure in question. It has previously been proposed that detection bias might explain the observed association between estrogens and endometrial cancer, as the estrogens may have induced bleeding and triggered diagnostic evaluation that may not otherwise have occurred (40Go). Clearly, this is now an unlikely explanation (41Go). It is also unlikely to affect unopposed estrogen and combination HRT differentially.

Misclassification bias with respect to outcome is unlikely, because case status was validated by review of medical records and pathology reports. Structured interviews minimized the opportunity for interviewer-related exposure misclassification. The potential for cases and controls to recall differentially past events and/or exposures in their lives, and consequently overreport or underreport certain items, cannot be excluded. However, several factors mitigating against recall bias in this study include our using structured interviews and state-of-the-art pharmacoepidemiology strategies to elicit drug histories; focusing on a drug class better recalled than most (42Go–44Go); focusing on a recall period comparable for cases and controls, as they were asked about drug exposures in the interval between menopause and the interview date; and our decision to interview cases after they returned home from the hospital to decrease the possibility that their recall and responses would be affected by the stress of the new diagnosis. Finally, the fact that we replicated results for known risk factors for endometrial cancer (45Go) was reassuring.

This study detected an attenuating effect of progestins on estrogen-induced endometrial cancer risk. The risk associated with postmenopausal use of any estrogen (i.e., periods with or without progestins) for 3 or more years compared with never use of HRT was lower than the risk associated with use of only unopposed estrogen, suggesting an attenuating effect of the progestins. Additional protection against endometrial cancer was conferred by use of combined estrogen and progestin only (of any duration) compared with never use of HRT. However, when considering duration (≥3 years) of the combination HRT, we found the protective effect to be not much greater than that from use for any duration. Thus, if HRT is to be used in women with an intact uterus, this study confirms the utility of adding progestins to the regimen.


   ACKNOWLEDGMENTS
 
This study was funded by grant PO1-CA77596 from the National Cancer Institute.

The authors want to thank the Project Manager for the Hospital Network Core, Elene Turzo, and the Project Manager for the Field Core, Desiree Burgh, for their incredible efforts in coordinating the logistic aspects of obtaining institutional review board approvals in participating hospitals and for ascertaining and recruiting the large number of subjects in this study. The authors also thank Karen Venuto, who managed the tracking database and the vast correspondence involved in such study, and Shawn Fernandes, who performed extensive quality control checks and helped with the development of the questionnaire database. The authors are also grateful for the cooperation of the hospitals in the Greater Delaware Valley and the support of the physicians who sponsored their study in these institutions, as without this help they could not have performed this study.

Jesse Berlin is a full-time employee of Johnson & Johnson Pharmaceutical Research and Development, L.L.C., and holds stock in Johnson & Johnson. Brian Strom has been a consultant for Wyeth Pharmaceuticals on other unrelated services.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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