Skip Navigation


American Journal of Epidemiology Advance Access originally published online on August 5, 2008
American Journal of Epidemiology 2008 168(6):563-570; doi:10.1093/aje/kwn168
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
168/6/563    most recent
kwn168v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Related articles in Am. J. Epidemiol.
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (7)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Epplein, M.
Right arrow Articles by Weiss, N. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Epplein, M.
Right arrow Articles by Weiss, N. S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Risk of Complex and Atypical Endometrial Hyperplasia in Relation to Anthropometric Measures and Reproductive History

Meira Epplein1,2,5, Susan D. Reed1,3,4, Lynda F. Voigt1,2, Katherine M. Newton2,4, Victoria L. Holt1,2 and Noel S. Weiss1,2

1 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
2 Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA
3 Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, WA
4 Group Health Center for Health Studies, Seattle, WA
5 Current affiliation: Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI

Correspondence to Dr. Meira Epplein, Epidemiology Program, Cancer Research Center of Hawaii, 1236 Lauhala Street, Suite 407, Honolulu, HI 96822 (e-mail: mepplein{at}crch.hawaii.edu).

Received for publication July 9, 2007. Accepted for publication February 15, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The authors sought to test the hypothesis that characteristics and exposures which influence the balance of estrogen and progesterone bear on the incidence of endometrial hyperplasia (EH), a noninvasive proliferation of the lining of the uterus. Cases included all female members of Group Health (Washington State) who were diagnosed with complex EH or EH with atypia during the period 1985–2003 and whose diagnoses were confirmed in a pathology review (n = 446). Controls were selected randomly from Group Health membership files and were matched to the cases by age and enrollment status at the reference date. An increased risk of EH was associated with increasing body mass index and nulliparity. There was a suggestion of a decreased risk of EH with atypia among current smokers. No association with diabetes or hypertension was found. The risk factors observed to be associated with EH in this study are similar to those associated with endometrial cancer. Whether these risk factors predispose women to cancer simply by increasing EH incidence or continue to augment cancer risk even after EH is present is currently unknown.

endometrial hyperplasia; endometrial neoplasms; endometrium; obesity; parity; smoking

Abbreviations: BMI, body mass index; CI, confidence interval


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Endometrial hyperplasia is a noninvasive proliferation of the lining of the uterus that results in a spectrum of glandular alterations (1–3). Endometrial hyperplasia is classified primarily as either simple or complex, based on the degree of architectural complexity as seen by glandular crowding (with back-to-back crowding in the case of complex hyperplasia), and with or without cytologic atypia—that is, nuclear irregularity, such as the loss of axial polarity; rounded, stratified nuclei; and prominent nucleoli (1, 2, 4). Hyperplasia with atypia is the least common type of hyperplasia and also the type most strongly associated with progression to endometrial cancer (5, 6). Typically, hyperplasia with atypia is treated by means of hysterectomy. In the United States, it is estimated that approximately one fourth of all women will have had a hysterectomy by age 60 years (7). Lepine et al. (7) estimated that approximately 15 percent of all hysterectomies performed in the United States (of a total of some 600,000 each year) are due to a diagnosis of endometrial hyperplasia or cancer.

It is believed that endometrial hyperplasia arises when estrogen, unopposed by progesterone, stimulates endometrial cell growth by binding to estrogen receptors in the nuclei of endometrial cells (8, 9). Exposure of these estrogen-induced proliferating cells to progesterone prompts the shedding of endometrial tissue both by reducing the number of estrogen receptors and by increasing the rate of conversion of estradiol to estrone, a less potent estrogen, through an increase in the activity of estradiol dehydrogenase (10, 11). Supporting this theory are the results of the randomized Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, where women assigned to receive estrogen-only hormone therapy were more likely to develop simple, complex, or atypical hyperplasia than women given a placebo (27.7 percent vs. 0.8 percent, 22.7 percent vs. 0.8 percent, and 11.8 percent vs. 0 percent, respectively) (12).

Factors related to an excess of circulating estrogen relative to circulating progesterone—such as obesity, late age at menopause, and nulliparity—have repeatedly been found to be predictors of endometrial carcinoma. Because endometrial hyperplasia often is an antecedent of cancer, these risk factors plausibly are related to endometrial hyperplasia as well. However, to our knowledge, only five studies have directly examined risk factors for endometrial hyperplasia other than hormone use (13–17). Of these five, only two addressed risk factors for the development of complex hyperplasia or hyperplasia with atypia (13, 17). Two of the three other studies included only women with abnormal menstrual bleeding as cases as well as controls (15, 16), resulting in a limited case definition (since asymptomatic cases were excluded) and an attenuation of any associations with factors related to both abnormal bleeding and hyperplasia. In the remaining study, investigators did not distinguish among hyperplasia types in the case group (14), and as a result the study may have included many women with simple hyperplasia, the most common type of endometrial hyperplasia and the type most likely to spontaneously regress (4, 12, 18, 19).

In fact, simple hyperplasia often spontaneously regresses; rarely does it progress to endometrial cancer (4, 19, 20). Complex hyperplasia and hyperplasia with atypia are more likely to progress to cancer and so are commonly treated with progestin or hysterectomy (4, 19, 20). In the present study, we sought to test the hypothesis that characteristics and exposures that influence the balance of endogenous estrogen and progesterone bear on the incidence of complex endometrial hyperplasia and endometrial hyperplasia with atypia.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
The setting for this study was Group Health, a Washington State mixed-model integrated health plan with over 500,000 enrollees. Potential cases included all female members of Group Health in Seattle/Puget Sound, Washington, over age 18 years, identified through text searches of the pathology database for diagnoses of complex endometrial hyperplasia or endometrial hyperplasia with atypia made between January 1, 1985, and December 31, 2003. All words related to the diagnoses of "complex endometrial hyperplasia" and "hyperplasia with atypia" (complex, adenomatous, atypia) were included in the text search. Any cases with a possible diagnosis were also included (e.g., "possible complex" or "atypia, cannot rule out well-differentiated endometrial carcinoma"). Cases were excluded if they had a previous diagnosis of endometrial cancer or had had a hysterectomy.

All pathology slides from the potential cases identified through Group Health pathology text searches were independently reviewed by two outside pathologists, utilizing standardized diagnostic criteria. When the two pathologists disagreed (22.2 percent of the time), the slides were read by a third pathologist. If the third pathologist disagreed with both of the initial diagnoses, the diagnosis was assigned by the senior pathologist. Of the 1,784 women diagnosed with possible complex endometrial hyperplasia or hyperplasia with atypia by Group Health who were not excluded for the above reasons, 1,236 were excluded because the study pathology review did not confirm the diagnosis of complex endometrial hyperplasia or endometrial hyperplasia with atypia. Specifically, these samples were categorized as: simple or no hyperplasia (n = 1,171); possible hyperplasia, but cannot assign diagnosis of complex or atypia (n = 7); adenocarcinoma (n = 34); and other—inadequate sample, nondiagnostic tissue, or no specimen available (n = 24). Analysis and discussion of the reproducibility of the diagnosis of endometrial hyperplasia is available elsewhere (21). Of the remaining 548 women with complex endometrial hyperplasia (n = 332) or hyperplasia with atypia (n = 216), 40 were excluded from this study because of missing medical charts, with a resulting 508 cases—311 complex and 197 atypia.

Controls were selected from the membership files of Group Health from 1985–2003. They were excluded for a previous diagnosis of endometrial hyperplasia as well as for the same reasons as the cases (a previous diagnosis of endometrial cancer or a previous hysterectomy). Controls were matched to cases by age at the reference date (±1 year) on a one-to-one basis and were required to have been enrolled in Group Health at the time of the case's diagnosis of endometrial hyperplasia. To ensure that the controls actually used Group Health as their primary care institution, we sought to choose only women who had made a visit to a Group Health provider (i.e., seen a medical professional for any reason) at least once in the 3 years prior to the reference date.

The Group Health pharmacy database was used to identify use of unopposed estrogen prior to 1 month before the inception date of the abnormal bleeding that led to the diagnosis of hyperplasia (or, if abnormal bleeding was not documented, prior to the 4 months before the diagnosis of hyperplasia). Subjects who had used estrogen-only hormone therapy, the best-known and strongest predictor of endometrial hyperplasia (and not the focus of the present analysis), for 60 days or more in the 6 months prior to the date of first symptoms of hyperplasia were excluded from this analysis, along with their matched control or case. This led to a loss of 12 percent of subjects (39 complex cases, 21 atypia cases, and two controls, as well as their matched counterparts), resulting in 446 cases for this study—271 women with complex endometrial hyperplasia and 175 women with endometrial hyperplasia with atypia—and their matched controls, or a total of 892 women.

Of the 446 cases in this study, we had knowledge of the presence of symptoms prior to diagnosis for 421 women (94 percent) (374 had an indication of abnormal uterine bleeding prior to the biopsy, while the other 47 reported abnormal menses). Another 13 women (3 percent) had their diagnosis determined after hysterectomy, and for the remaining 12 women (3 percent) we did not have information on the indication for biopsy.

Data collection
Trained medical abstractors obtained data on the following variables of interest from the paper and electronic medical records of cases and controls: menstrual characteristics and age or year of menopause, parity (the number of times a woman gave birth at or after 20 weeks' gestation), race/ethnicity, smoking status at the reference date, and medical history, including a diagnosis of diabetes mellitus or hypertension (the presence of elevated or high blood pressure that was treated with medication or lifestyle changes). If abnormal bleeding was noted on or prior to the reference date, abstractors recorded the date of the first medical visit for abnormal bleeding prior to the reference date and the number of months of abnormal bleeding prior to the reference date. For subjects who were missing information on abnormal bleeding (n = 72), a date for inception of abnormal bleeding was assigned as 3 months prior to the reference date (the median duration of abnormal bleeding among the cases). Additionally, abstractors obtained data on height and weight, for calculation of body mass index (BMI; weight (kg)/height (m)2) at the reference date, and also previous weight at least 1 year prior to the reference date. After 100 medical chart abstractions had been completed, a 5 percent random sample of charts was reabstracted to verify consistency.

We queried the Group Health enrollment database to determine dates of enrollment for each study subject, as well as zip code at the reference date (or the closest time thereto). We then used the study subjects' zip codes to find the median income in their geographic region, as determined by the 1990 US Census (Summary Tape File 3). Because of confidentiality laws, information on median income was not available for zip code areas where the population was deemed too small by the US Census Bureau.

Data analysis
In the initial analysis, we evaluated associations between complex endometrial hyperplasia and endometrial hyperplasia with atypia and the following potential risk factors: BMI at least 1 year prior to the reference date (for the 5 percent of study subjects for whom this weight was not available, weight recorded in the year before the reference date was used); parity; smoking; diabetes; and hypertension. These potential risk factors, as well as race, zip code (as a proxy for socioeconomic factors), and years enrolled in Group Health (smoothed to remove gaps of 1–2 months), were included in a given analysis only when they were related both to the specific exposure under consideration and to the outcome of endometrial hyperplasia, without being in the causal pathway.

We used conditional logistic regression to test the association of the potential risk factors with complex hyperplasia and hyperplasia with atypia while accounting for the matching of cases and controls by age and enrollment status at the reference date. Analyses were performed first for all women and then stratified by age, as a proxy for menopausal status, since we did not feel confident about recorded age at menopause among women with abnormal bleeding patterns related to endometrial hyperplasia. Women were categorized as less than 52 years of age or 52 years of age or older (52 was the median age at menopause in the control group). Adjusted odds ratios and 95 percent confidence intervals were calculated for each parameter estimate. Tests for linear trends in the odds ratios (including the reference group) associated with obesity and parity were conducted using likelihood ratio tests with a chi-squared distribution (22).

All analyses were performed with the STATA software package, version 8.0 (Stata Corporation, College Station, Texas).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Women with complex endometrial hyperplasia and hyperplasia with atypia were similar to their age-matched controls in terms of race, median income of residential zip code, and years enrolled in Group Health (table 1).


View this table:
[in this window]
[in a new window]

  		TABLE 1. Demographic characteristics of cases and controls, Group Health Cooperative, Seattle/Puget Sound, Washington, 1985–2003

 
The incidence of endometrial hyperplasia rose with increasing BMI. The strongest associations were for women younger than age 52 years. Compared with women who were not overweight (BMI ≤24.9) and after adjustment for parity, among this younger group, overweight women (BMI 25–29.9) had a threefold increased risk of complex hyperplasia (95 percent confidence interval (CI): 1.2, 7.2) and a 2.3-fold increased risk of hyperplasia with atypia (95 percent CI: 0.7, 7.9) (table 2). Obese women (BMI 30–39.9) had a 4.6-fold increase in risk of complex hyperplasia (95 percent CI: 2.1, 10.3) and a 3.7-fold increase in risk of hyperplasia with atypia (95 percent CI: 1.0, 13.8). Morbidly obese women (BMI ≥40) had a 23-fold increase in risk of complex hyperplasia (95 percent CI: 6.6, 79.8) and a 13-fold increase in risk of hyperplasia with atypia (95 percent CI: 1.9, 86.9).


View this table:
[in this window]
[in a new window]

  		TABLE 2. Relation of endometrial hyperplasia to several potential risk factors, by menopausal status and type of hyperplasia, Group Health Cooperative, Seattle/Puget Sound, Washington, 1985–2003

 
Adjusting for BMI, women who had given birth to a child had a lower risk of endometrial hyperplasia than nulliparous women (table 2). For both complex endometrial hyperplasia and endometrial hyperplasia with atypia, this reduced risk was most apparent in women under 52 years of age.

No association was found between smoking status and risk of complex endometrial hyperplasia. There was a suggestion of a decreased risk of endometrial hyperplasia with atypia among current smokers (table 2).

No associations were found between the risk of complex endometrial hyperplasia and a diagnosis of diabetes or the presence of hypertension. Among women aged 52 years or more, there was a suggestion of an increased risk of endometrial hyperplasia with atypia among those diagnosed with diabetes (odds ratio = 4.0, 95 percent CI: 0.8, 19.1) and a decreased risk of hyperplasia with atypia among those with hypertension (odds ratio = 0.5, 95 percent CI: 0.3, 1.0) (table 2).

We also performed the analyses after eliminating cases (and matched controls) who had been diagnosed with invasive endometrial carcinoma within 8 weeks of their index biopsy (n = 41; data not shown). The results differed little from those presented in table 2.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In the present study, a strong positive association was found between increasing BMI and risk of complex endometrial hyperplasia and endometrial hyperplasia with atypia, as was generally observed in the two other comparable studies that examined risk factors for endometrial hyperplasia (13, 17). Defining obesity as a BMI greater than or equal to 30, and using as a referent category women with a BMI less than 30, an Italian case-control study that included 129 women with complex endometrial hyperplasia without atypia obtained odds ratios of 2.4 (95 percent CI: 1.0, 5.9) among premenopausal women and 4.3 (95 percent CI: 1.7, 10.5) among postmenopausal women (17). Using similar definitions, a case-control study in Canada that included 149 women (62 premenopausal and 87 postmenopausal) with adenomatous endometrial hyperplasia (all endometrial hyperplasia excluding simple) obtained odds ratios of 0.2 (95 percent CI: 0.1, 0.8) among premenopausal women and 3.2 (95 percent CI: 1.4, 7.5) among postmenopausal women (13). Both of the previous studies relied on self-reporting (which is less accurate than measurement) for height and weight, and the Italian study used hospital-based controls (women who were "admitted for conditions other than gynecological, malignant, or hormone-related"), which would have attenuated an association with increasing BMI to the extent that the controls were heavier than women in the general population.

Obesity could lead to the development of endometrial hyperplasia by increasing the concentration of circulating estrogens and thus stimulation of growth of the endometrium. This could happen in several ways: by decreasing levels of circulating sex hormone-binding globulin (23) or by increasing the conversion of androstenedione to estrone that occurs with increased adipose tissue (24). Premenopausal women who are obese could be at additional risk, since they are more likely to have periods of anovulation and therefore lower progesterone levels (25, 26), which increases their risk of endometrial proliferation and inadequate menstrual shedding of the endometrium.

In this study, we observed that the risks of both complex hyperplasia and hyperplasia with atypia decreased in proportion to the number of deliveries, at least among women younger than age 52 years. The reduction in risk was particularly great for women who had had three or more children—on the order of 70 percent and 90 percent decreased risks for complex hyperplasia and hyperplasia with atypia, respectively. This finding contradicts that of the one previous study on the etiology of endometrial hyperplasia that examined an association with parity (17). That study suggested a possible increasing risk with greater numbers of children, with odds ratios of 1.6 (95 percent CI: 0.7, 3.5) and 1.8 (95 percent CI: 0.9, 3.6) for parities of 1 and ≥2, respectively, as compared with nulliparous women (17). Studies examining the association of parity with endometrial cancer have consistently found an inverse relation between risk and number of births, with an even greater reduction in risk among women younger than 50 or 55 years of age (27, 28). In a study of women without endometrial hyperplasia or endometrial cancer, Lambe et al. (29) observed decreasing levels of free estradiol and increasing levels of sex hormone-binding globulin in the postmenopausal period associated with increasing parity. This hormonal milieu of low estradiol and high sex hormone-binding globulin would be expected to not stimulate endometrial cell growth. To our knowledge, no such study has been conducted among premenopausal women, but one explanation that has been offered for the even greater reduction in endometrial cancer risk with increasing parity among premenopausal women is that any malignant or premalignant cells present in the mucosal lining of the endometrium are shed during delivery (30).

In the present study, there was a suggestion of a decrease in risk of endometrial hyperplasia with atypia among current smokers. Smoking may decrease the rate of conversion of androgens to estrogens by blocking the aromatase enzyme (31). Smoking is also associated with earlier menopause and lower body fat, both of which are associated with a reduced risk of endometrial hyperplasia and could be the underlying basis for the association. Smoking has been associated with a reduced risk of endometrial cancer in most studies, with the reduction in risk being especially strong among postmenopausal women (27).

Limitations of this study relate primarily to the limited amount of detailed information we were able to obtain from medical record abstraction. For example, on average, the weight assigned to study subjects was recorded 5 years prior to the reference date. However, this is possibly not representative of weight during the etiologically relevant time period, since retrospective studies of women who underwent endometrial biopsies have found that progression from normal endometrium to complex hyperplasia may take 7 years or longer, and progression to endometrial hyperplasia with atypia may take approximately 10 years (32–34). Information on smoking history was unavailable from the medical records for 1 percent of controls and 7 percent of cases, and details on smoking history—including both intensity (dose) and duration—were not systematically present in the medical records. Similarly, information on the severity and treatment of both diabetes and hypertension was not obtained. Information on age at menopause was collected, but the specific year or age of the last menstrual period was difficult, if not impossible, to assess because of issues surrounding abnormal menstrual bleeding. By omitting this potential risk factor from our analysis, we may have allowed residual confounding.

Another potential limitation of this study is that some controls may have had as-yet-undiagnosed complex endometrial hyperplasia or endometrial hyperplasia with atypia. However, in a study in which endometrial biopsy specimens were obtained from 2,964 asymptomatic peri- and postmenopausal women who were not currently on hormone therapy, Drury and Louis (35) found that less than 1 percent had a hyperplastic endometrium. Because obese women tend to delay seeing their doctor for general health-care visits and gynecologic examinations (36, 37), it is likely that the degree of underdiagnosis is greatest in this group of women. In this situation, case underascertainment would conservatively bias the results toward a conclusion of no association with obesity. In theory, a control group could have been selected from women undergoing endometrial biopsy who were found not to have hyperplasia. However, the distribution of hormone-related characteristics in such a group almost certainly would not reflect that of women in general.

There exists an additional concern: because a number of retrospective studies have found a large percentage (17–50 percent) of concomitant endometrial cancer in patients with atypical endometrial hyperplasia (6, 38–44), the associations found in this study may have arisen primarily from their relation with endometrial cancer. However, with random sampling of biopsies, misclassifying by either overclassifying or underclassifying is possible, and we excluded anyone who was classified as having cancer by either community pathologists or research pathologists. Additionally, misclassification of simple hyperplasia and well-differentiated carcinoma—Group Health diagnoses that were not analyzed by independent research pathologists—is possible and was not accounted for in this study. Lastly, while the pathologic diagnoses for cases in this study were assigned by independent research pathologists who were unaware of the Group Health diagnosis, misclassification errors may still exist.

The risk factors found to be associated with endometrial hyperplasia in this study are similar to those associated with endometrial cancer. Whether these risk factors predispose women to cancer simply by increasing the incidence of hyperplasia or continue to augment cancer risk even after hyperplasia is present is unknown at the present time.


   ACKNOWLEDGMENTS
 
The authors acknowledge support from the Group Health Center for Health Studies (Seattle, Washington) and the National Cancer Institute (Bethesda, Maryland) (grants R01HD044813 and K05CA092002).

The authors thank Kay Hager, Kelly Ehrlich, Kay Byron, Walter Clinton, Carol Brandford, Kathy Plant, and Kevin Beverly for their technical and organizational assistance.

Conflict of interest: none declared.


   NOTES
 
Editor's note: An invited commentary on this article appears on page 571, and the authors' response appears on page 575.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. Kurman RJ. Blaustein's pathology of the female genital tract. (1994) New York, NY: Springer-Verlag.
  2. Silverberg SG, Kurman RJ, Nogales F, et al. Tumours of the uterine corpus: epithelial tumours and related lesions. In: Pathology and genetics: tumours of the breast and female genital organs—Tavassoli FA, Devilee P, eds. (2003) Lyon, France: IARC Press. 221–32.
  3. Mazur MT, Kurman RJ. Diagnosis of endometrial biopsies and curettings: a practical approach. (2005) New York, NY: Springer Publishing Company.
  4. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia: a long-term study of ‘untreated’ hyperplasia in 170 patients. Cancer (1985) 56:403–12.[CrossRef][Web of Science][Medline]
  5. Lindahl B, Willen R. Spontaneous endometrial hyperplasia: a prospective, 5 year follow-up of 246 patients after abrasio only, including 380 patients followed-up for 2 years. Anticancer Res (1994) 14:2141–6.[Web of Science][Medline]
  6. Hunter JE, Tritz DE, Howell MG, et al. The prognostic and therapeutic implications of cytologic atypia in patients with endometrial hyperplasia. Gynecol Oncol (1994) 55:66–71.[CrossRef][Web of Science][Medline]
  7. Lepine LA, Hillis SD, Marchbanks PA, et al. Hysterectomy surveillance—United States, 1980 –1993. MMWR CDC Surveill Summ (1997) 46:1–15.[Medline]
  8. Gusberg SB. Hormone-dependence of endometrial cancer. Obstet Gynecol (1967) 30:287–93.[Web of Science][Medline]
  9. Anderson JN, Peck EJJ, Clark JH. Estrogen-induced uterine responses and growth: relationship to receptor estrogen binding by uterine nuclei. Endocrinology (1975) 96:160–7.[Abstract/Free Full Text]
  10. Tseng L, Gurpide E. Induction of endometrial estradiol dehydrogenase by progestins. Endocrinology (1975) 97:825–33.[Abstract/Free Full Text]
  11. King RJ, Whitehead MI, Campbell S, et al. Effect of estrogen and progestin treatments on endometria from postmenopausal women. Cancer Res (1979) 39:1094–101.[Abstract/Free Full Text]
  12. The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA (1996) 275:370–5.[Abstract/Free Full Text]
  13. Kreiger N, Marrett LD, Clarke EA, et al. Risk factors for adenomatous endometrial hyperplasia: a case-control study. Am J Epidemiol (1986) 123:291–300.[Abstract/Free Full Text]
  14. Baanders-van Halewyn EA, Blankenstein MA, Thijssen JH, et al. A comparative study of risk factors for hyperplasia and cancer of the endometrium. Eur J Cancer Prev (1996) 5:105–12.[CrossRef][Medline]
  15. Farquhar CM, Lethaby A, Sowter M, et al. An evaluation of risk factors for endometrial hyperplasia in premenopausal women with abnormal menstrual bleeding. Am J Obstet Gynecol (1999) 181:525–9.[CrossRef][Web of Science][Medline]
  16. Weber AM, Belinson JL, Piedmonte MR. Risk factors for endometrial hyperplasia and cancer among women with abnormal bleeding. Obstet Gynecol (1999) 93:594–8.[CrossRef][Web of Science][Medline]
  17. Ricci E, Moroni S, Parazzini F, et al. Risk factors for endometrial hyperplasia: results from a case-control study. Int J Gynecol Cancer (2002) 12:257–60.[CrossRef][Web of Science][Medline]
  18. Terakawa N, Kigawa J, Taketani Y, et al. The behavior of endometrial hyperplasia: a prospective study. J Obstet Gynaecol Res (1997) 23:223–30.[Medline]
  19. Ferenczy A, Gelfand M. The biologic significance of cytologic atypia in progestogen-treated endometrial hyperplasia. Am J Obstet Gynecol (1989) 160:126–31.[Web of Science][Medline]
  20. Kurman RJ, Felix JC, Archer DF, et al. Norethindrone acetate and estradiol-induced endometrial hyperplasia. Obstet Gynecol (2000) 96:373–9.[CrossRef][Web of Science][Medline]
  21. Allison KH, Reed SD, Voigt LF, et al. Diagnosing endometrial hyperplasia: why is it so difficult to agree? Am J Surg Pathol (2008) 32:691–8.[CrossRef][Web of Science][Medline]
  22. Breslow NE, Day NE. Statistical methods in cancer research. Vol 1. In: The analysis of case-control studies (1980) Lyon, France: International Agency for Research on Cancer. (IARC Scientific Publication no. 32).
  23. Kaye SA, Folsom AR, Soler JT, et al. Association of body mass and fat distribution with sex hormone concentrations in postmenopausal women. Int J Epidemiol (1991) 20:151–6.[Abstract/Free Full Text]
  24. MacDonald PC, Edman CD, Hemsell DL, et al. Effect of obesity on conversion of plasma androstenedione to estrone in postmenopausal women with and without endometrial cancer. Am J Obstet Gynecol (1978) 130:448–55.[Web of Science][Medline]
  25. Sherman BM, Korenman SG. Measurement of serum LH, FSH, estradiol and progesterone in disorders of the human menstrual cycle: the inadequate luteal phase. J Clin Endocrinol Metab (1974) 39:145–9.[Abstract/Free Full Text]
  26. Teitelman M, Grotegut CA, Williams NN, et al. The impact of bariatric surgery on menstrual patterns. Obes Surg (2006) 16:1457–63.[CrossRef][Web of Science][Medline]
  27. Cook LS, Weiss NS, Doherty JA, et al, Endometrial cancer. Cancer epidemiology and prevention. 3rd ed. Schottenfeld D, Fraumeni JF Jr, eds. (2006) New York, NY: Oxford University Press. 1027–43.
  28. Brinton LA, Sakoda LC, Lissowska J, et al. Reproductive risk factors for endometrial cancer among Polish women. Br J Cancer (2007) 96:1450–6.[Web of Science][Medline]
  29. Chubak J, Tworoger SS, Yasui Y, et al. Associations between reproductive and menstrual factors and postmenopausal sex hormone concentrations. Cancer Epidemiol Biomarkers Prev (2004) 13:1296–301.[Abstract/Free Full Text]
  30. Lambe M, Wuu J, Weiderpass E, et al. Childbearing at older age and endometrial cancer risk (Sweden). Cancer Causes Control (1999) 10:43–9.[CrossRef][Web of Science][Medline]
  31. Tankó LB, Christiansen C. An update on the antiestrogenic effect of smoking: a literature review with implications for researchers and practitioners. Menopause (2004) 11:104–9.[CrossRef][Web of Science][Medline]
  32. Hertig AT, Sommers SC. Genesis of endometria carcinoma: study of prior biopsies. Cancer (1949) 2:946–56.[CrossRef][Web of Science][Medline]
  33. Beutler HK, Dockerty MB, Randall LM. Precancerous lesions of the endometrium. Am J Obstet Gynecol (1963) 86:433–43.[Web of Science][Medline]
  34. Ferenczy A, Gelfand M. Hyperplasia vs. neoplasia: two tracks for the endometrium? Contemp Obstet Gynecol (1986) 28:79–96.
  35. Korhonen MO, Symons JP, Hyde BM, et al. Histologic classification and pathologic findings for endometrial biopsy specimens obtained from 2964 perimenopausal and postmenopausal women undergoing screening for continuous hormones as replacement therapy (CHART 2 Study). Am J Obstet Gynecol (1997) 176:377–80.[CrossRef][Web of Science][Medline]
  36. Drury CA, Louis M. Exploring the association between body weight, stigma of obesity, and health care avoidance. J Am Acad Nurse Pract (2002) 14:554–61.[CrossRef][Medline]
  37. Fontaine KR, Faith MS, Allison DB, et al. Body weight and health care among women in the general population. Arch Fam Med (1998) 7:381–4.[Abstract/Free Full Text]
  38. Kurman RJ, Norris HJ. Evaluation of criteria for distinguishing atypical endometrial hyperplasia from well-differentiated carcinoma. Cancer (1982) 49:2547–59.[CrossRef][Web of Science][Medline]
  39. Gusberg SB, Kaplan AL. Precursors of corpus cancer: adenomatous hyperplasia as stage 0 carcinoma of the endometrium. Am J Obstet Gynecol (1963) 87:662–78.[Web of Science][Medline]
  40. Tavassoli FA, Kraus FT. Endometrial lesions in uteri resected for atypical endometrial hyperplasia. Am J Clin Pathol (1978) 70:770–9.[Web of Science][Medline]
  41. King A, Seraj IM, Wagner RJ. Stromal invasion in endometrial adenocarcinoma. Am J Obstet Gynecol (1984) 149:10–14.[Web of Science][Medline]
  42. Janicek MF, Rosenshein NB. Invasive endometrial cancer in uteri resected for atypical endometrial hyperplasia. Gynecol Oncol (1994) 52:373–8.[CrossRef][Web of Science][Medline]
  43. Widra EA, Dunton CJ, McHugh M, et al. Endometrial hyperplasia and the risk of carcinoma. Int J Gynecol Cancer (1995) 5:233–5.[CrossRef][Web of Science][Medline]
  44. Trimble CL, Kauderer J, Zaino R, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer (2006) 106:812–19.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?

Related articles in Am. J. Epidemiol.:

Invited Commentary: Endometrial Hyperplasia—Getting Back to Normal
James V. Lacey, Jr.
Am. J. Epidemiol. 2008 168: 571-574. [Abstract] [FREE Full Text]  

Epplein et al. Respond to "Endometrial Hyperplasia—Getting Back to Normal"
Meira Epplein, Susan D. Reed, Lynda F. Voigt, Katherine M. Newton, Victoria L. Holt, and Noel S. Weiss
Am. J. Epidemiol. 2008 168: 575-576. [Extract] [FREE Full Text]  



This article has been cited by other articles:


Home page
 Am J EpidemiolHome page
J. V. Lacey Jr.
Invited Commentary: Endometrial Hyperplasia--Getting Back to Normal
Am. J. Epidemiol., September 15, 2008; 168(6): 571 - 574.
[Abstract] [Full Text] [PDF]

Home page
 Am J EpidemiolHome page
M. Epplein, S. D. Reed, L. F. Voigt, K. M. Newton, V. L. Holt, and N. S. Weiss
Epplein et al. Respond to "Endometrial Hyperplasia--Getting Back to Normal"
Am. J. Epidemiol., September 15, 2008; 168(6): 575 - 576.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
168/6/563    most recent
kwn168v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Related articles in Am. J. Epidemiol.
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (7)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Epplein, M.
Right arrow Articles by Weiss, N. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Epplein, M.
Right arrow Articles by Weiss, N. S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?