- Email: [email protected]
Endometrial histology in severely obese bariatric surgery candidates: an exploratory analysis
Surgery for Obesity and Related Diseases ] (2015) 00–00
Original article
Endometrial histology in severely obese bariatric surgery candidates: an exploratory analysis Aiym Kaiyrlykyzy, M.D.a, Kyle E. Freese, M.P.H.b,c, Esther Elishaev, M.D.d, Dana H. Bovbjerg, Ph.D.e, Ramesh Ramanathan, M.D.f, Giselle G. Hamad, M.D.f, Carol McCloskey, M.D.f, Andrew D. Althouse, Ph.D.c, Marilyn Huang, M.D., M.S.c, Robert P. Edwards, M.D.c, Faina Linkov, Ph.D.b,c,* a Center for Life Sciences, Nazarbayev University, Astana, Kazakhstan Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA c Department of Obstetrics, Gynecology & Reproductive Sciences, Magee-Womens Research Institute, Pittsburgh, PA d Department of Pathology, Magee-Womens Hospital, Pittsburgh, PA e University of Pittsburgh Cancer Institute, Pittsburgh, PA f Division of General Surgery, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA Received July 28, 2014; accepted December 12, 2014 b
Abstract
Background: Endometrial pathology risk has been linked to obesity; however, little is known of its prevalence in severely obese women not seeking care for endometrial pathology associated symptoms. This pilot study was designed to explore the frequency and risk factors associated with endometrial pathology in cancer-free, severely obese, bariatric surgery candidates using the Pipelle endometrial sampling technique (SureFlex Preferred Curette, Bioteque America, Inc, New Taipei City, Taiwan). Methods: Twenty-nine severely obese bariatric surgery candidates with intact uteruses and no history of endometrial cancer or endometrial ablation were included in this subanalysis from a larger cohort of 47. Endometrial samples were obtained using a Pipelle endometrial suction curette at a single time point before surgery. Logistic regression was used to assess the relationship between body mass index and endometrial pathology when adjusting for age and race. Results: Of the 29 successful biopsies, 8 (27.6%) were classified as abnormal endometrium: 1 was classified as complex atypical hyperplasia, 1 was classified as hyperplasia without atypia, 4 samples were identified with endometrial polyps, and 2 samples were identified with metaplasia. None presented with cancer. Increasing body mass index was significantly associated with higher risk of abnormal endometrium (OR ¼ 1.19, 95% CI [1.03–1.36], P ¼ .01). Conclusions: The findings in this sample suggest that obesity may be associated with increased risk of having undiagnosed endometrial pathology. More thorough examination of relationships between levels of obesity and endometrial pathology are needed to better characterize high cancer risk groups who may benefit from introducing new screening measures. (Surg Obes Relat Dis 2015;]:00–00.) r 2015 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Bariatric surgery; Endometrial cancer; Endometrial hyperplasia; Endometrial polyps; Obesity; Pipelle sampling
This study was funded by the American Cancer Society (MRSG-10-07901-CPPB) and the Scaife Foundation. Biostatistical support was provided by Andrew D. Althouse, Ph.D. * Correspondence: Faina Linkov, Ph.D., M.P.H., Department of Obstetrics, Gynecology & Reproductive Sciences, University of Pittsburgh, 3380 Boulevard of Allies, Room 323, Pittsburgh, PA 15217. E-mail: [email protected]
Endometrial cancer (EC) incidence has been increasing since 2007 and is the most common gynecologic cancer in the United States [1–3]. The American Cancer Society estimates that at least 52,630 new cases of EC will be diagnosed in 2014 [4]. Risk factors for EC, as well as its
http://dx.doi.org/10.1016/j.soard.2014.12.010 1550-7289/r 2015 American Society for Metabolic and Bariatric Surgery. All rights reserved.
2
A. Kaiyrlykyzy et al. / Surgery for Obesity and Related Diseases ] (2015) 00–00
precursor, endometrial hyperplasia (EH), include high levels of unopposed estrogen, low physical activity [5], and obesity [6,7]. A large, retrospective cohort study exploring the association between EC risk and specific body mass index (BMI) found that for every 1 kg/m2 increase in BMI, there was an 11% increase in the likelihood of EC diagnosis [8]. A meta-analysis of BMI and incident EC revealed an overall risk ratio of 1.6 for every 5 units of BMI increase [9]. EH, particularly complex hyperplasia with atypia, is a wellknown precursor for EC [6,10]. Risk factors for EH are similar to those for EC, including increased BMI [11]. Compared with women with normal BMI, previously published work suggests that obese women (BMI 30–39.9) had a 4.6-fold increase in risk of complex hyperplasia (95% CI: 2.1, 10.3) and a 3.7-fold increase in risk of hyperplasia with atypia (95% CI: 1.0, 13.8) [12]. Morbidly obese women (BMI Z40) had a 23-fold increase in risk of complex hyperplasia (95% CI: 6.6, 79.8) and a 13-fold increase in risk of hyperplasia with atypia (95% CI: 1.9, 86.9) [12]. Approximately 30% of women with untreated complex hyperplasia with atypia progress to carcinoma, so timely diagnosis of EH is crucial [13]. In addition to hyperplasia, it is important to know the prevalence of endometrial polyps and metaplasia in the general population of obese women, because those conditions have been associated with EC in previous research [14,15]. Although asymptomatic women generally are not screened for EC, endometrial Pipelle sampling can potentially be used as a routine screening tool in the outpatient setting for identifying endometrial pathologies [16,17]. Because previous literature has shown endometrial Pipelle sampling to be successful in obtaining sufficient tissue [18] and because the sampling can be done on outpatient basis without the use of anesthetics, Pipelle biopsy has been used in this population. In previous studies of untreated, asymptomatic, severely obese women (BMI 435), Argenta et al. found that the prevalence of endometrial hyperplasia is approximately 6.8% [19,20]. Viola et al. found endometrial cancer or hyperplasia in 8.9% of asymptomatic overweight or obese women, both pre -and post- menopausal, undergoing Pipelle biopsy [21]. Although previous studies provided important information on the prevalence of hyperplasia and cancer in asymptomatic women, they did not report information on the prevalence of other pathologies (such as polyps and metaplasia) and they were also limited by the inclusion of asymptomatic women only. The primary objective of the present study was to describe the prevalence of a wide spectrum of endometrial pathologies in a general cohort of cancer-free, severely obese women considering bariatric surgery.
Materials and methods Study participants Severely obese (BMI Z35), female bariatric surgery candidates were recruited from Magee-Women’s Hospital
of the University of Pittsburgh Medical Center Health System (UPMC). Patients were considered eligible to participate in this investigation if they were at least 29 years old (because of a suspected lower prevalence of endometrial pathologies in the younger age group), enrolled in a bariatric surgery program, and expected to undergo bariatric surgery (Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, or sleeve gastrectomy) within 6 months of recruitment. Exclusion criteria included prior endometrial ablation or hysterectomy, severe inflammatory or autoimmune diseases (as these samples were collected from larger study investigating inflammatory biomarkers), or refusal to consent to endometrial biopsy. Patients were not excluded on the basis of gynecologic symptoms such as abnormal menstrual bleeding; however, most patients were asymptomatic. This subanalysis was restricted to women with successful/sufficient endometrial biopsies (biopsies yielding sufficient endometrial tissue for pathology analysis). To justify the focus on participants with successful biopsies, these patients (n ¼ 29) were compared with those without successful biopsies (n ¼ 18) using Wilcoxon tests for continuous variables and χ2 tests for categorical variables to ensure that there was no substantial difference between the groups. All study-related procedures were performed at the Clinical and Translational Research Center of MageeWomen’s Hospital of UPMC by trained clinical and/or research staff. The University of Pittsburgh Institutional Review Board approved this study, and all patients provided written, informed consent (Protocol #PRO08080042).
Measurements Two experienced clinical staff members (a gynecologic oncologist and a physician assistant) obtained endometrial samples using a Pipelle endometrial suction curette in accordance with the manufacturer’s instructions. Cervical ripening agents were not administered before biopsies. Acquired specimens were formalin-fixed, embedded in paraffin, sectioned, and stained using standard hematoxylin and eosin stain preparation, then evaluated by 2 independent pathologists with expertise in gynecologic pathology, who were blinded to the patients’ health histories, age, BMI, and identifying characteristics. A third (senior) pathologist addressed any discrepancies between the findings of the 2 pathologists. Patients who evidenced pathology were referred to a gynecologist or gynecologic oncologist (as appropriate) for follow-up care. A research registered nurse collected anthropometric measurements, during which participants wore light clothing and no shoes. Waist and hip circumferences were measured to the nearest centimeter using a nonstretchable tape. Height was recorded to the nearest inch by a standardized wall-mounted stadiometer. A Tanita body
Endometrial Histology in Severely Obese Women / Surgery for Obesity and Related Diseases ] (2015) 00–00
composition analyzer (Model TBF-310, Tanita Corporation of America [Arlington Heights, IL]) was used to assess weight, total body fat, and percent body fat. Reproductive histories, including gravidity, parity, polycystic ovary syndrome (PCOS), menstrual history, and desired fertility were obtained using a validated reproductive baseline health survey, which has been used previously in large, multicenter studies targeting bariatric surgery patients [22]. Information on co-morbidities was obtained from a general health questionnaire developed and validated by Burke et al. for previously published interventions targeting severely obese individuals [23,24]. Statistical methods Data analysis was performed using SAS Version 9.3 (SAS Institute Inc., Cary, NC) [25]. Descriptive statistics were reported as median (range) for continuous variables and n (%) for categorical variables. The Wilcoxon rank-sum test (continuous variables) and Fisher’s exact test (categorical variables) were used to compare women with identified pathologies (e.g., hyperplasia with atypia, hyperplasia without atypia, metaplasia, or endometrial polyps) with pathology-free women. Differences in race, age, body composition, and other characteristics were evaluated. Logistic regression was used to assess the relationship between BMI and endometrial pathology when adjusting for age and race. P values less than .05 were considered statistically significant. Results Baseline characteristics of the 29 participants with successful biopsies are listed in Table 1. The median age
3
of the patients was 39 (30–62) years, most (68.9%) of whom reported their racial/ethnic background as white, and the median BMI was 46.4 kg/m2 (35.7–66.1). Median gravidity was 2 prior pregnancies, ranging from 0 (never been pregnant) to 12. Thirteen women reported irregular menses and 5 reported being previously diagnosed with PCOS by a healthcare provider. Five women reported a history of hormone use, mainly for contraception, with only one woman reporting prior use of hormone replacement therapy. Common co-morbid conditions reports by participants included hypertension (48%), diabetes (14%), thyroid disease (17%), heart problems (7%), and cancer (7%). Comparison of the 29 participants with successful biopsies to the 18 participants with failed biopsies showed that there were no differences in age (P ¼ .80), race (P ¼ 1.00), BMI (P ¼ .51), waist circumference (P ¼ .62), reproductive history (P ¼ .92), menopausal status (P ¼ .29), regularity of periods (P ¼ .76), or history of hormone use (P ¼ 1.00). The distribution of endometrial histologies is shown in Fig. 1. Eight patients (27.6%, 95% CI [11.3%–43.8%]) had evidence of abnormal endometrium: 2 patients showed evidence of hyperplasia, 2 showed evidence of metaplasia, and 4 had an endometrial polyp. Proliferative pattern was the most common histology (21.6%), and 4 samples revealed a hormonal effect associated with birth control manifested by pseudodecidualized stroma and inactive glands, characteristic of progestin effect. No participants had evidence of EC. Table 1 provides general characteristics of the study population and compares groups by the presence of endometrial pathology. Patients with abnormal endometrium (endometrial hyperplasia with/without atypia or
Table 1 General characteristics of study participants, as well as characteristics stratified by histopathological analysis of endometrial biopsies Characteristic
Successful biopsy (n ¼ 29)
Normal endometrium (n ¼ 21)
Abnormal endometrium (n ¼ 8)
Age (years) Ethnicity White Black Preoperative BMI (kg/m2) Total fat mass (kg) Body fat percentage Waist circumference (cm) Waist-hip ratio Endometrial thickness† Number of prior pregnancies Premenopausal Irregular periods Prior Diagnosis of PCOS History of hormone use
39 (30–62)
38 (31–62)
41 (30–57)
20 (68.9%) 9 (31.1%) 46.4 (35.7–66.1) 67.5 (40.0–107.5) 52.4 (45.3–67.2) 133.9 (106–168) .90 (.79–1.03) 13.0 (2.9–45.6) 2 (0–12) 24 (82.8%) 13 (44.8%) 5 (17.2%) 5 (17.2%)
14 (66.7%) 7 (33.3%) 45.0 (35.7–63.9) 62.3 (40.0–99.8) 50.4 (43.4–60.4) 125 (104–167) .90 (.80–.99) 11.4 (8.3–33.5) 2 (0–8) 18 (85.7%) 8 (40.0%) 3 (14.3%) 5 (23.8%)
6 (75%) 2 (25%) 54.9 (44.8–66.1) 79.9 (67.6–107.5) 54.3 (46.7–67.2) 139 (127–155) .90 (.85–1.00) 13.3 (2.9–45.6) 2 (0–12) 6 (75.0%) 5 (62.5%) 2 (25.0%) 0 (0%)
Abbreviations: BMI ¼ body mass index; PCOS ¼ polycystic ovary syndrome. Note: Continuous variables described by medians (ranges); categorical variables described by n (%). * P-values compare those with abnormal endometrium versus those with normal endometrium. † N ¼ 13 for endometrial thickness (10 with normal endometrium, 3 with abnormal endometrium) due to missing data.
P value* .79 1.00
o .01 o .01 .05 .01 .85 1.00 .63 .60 .16 .58 .29
A. Kaiyrlykyzy et al. / Surgery for Obesity and Related Diseases ] (2015) 00–00
4
Fig. 1. Distribution of endometrial biopsy findings among those undergoing endometrial Pipelle sampling in an outpatient setting.
endometrial polyps) had significantly higher preoperative BMIs (45.0 versus 54.9, P o .01), body fat mass (62.3 kg versus 79.9 kg, P o .01), and waist circumference (125 cm versus 139 cm, P ¼ .01). Both patients diagnosed with hyperplasia in this sample were Class 3 obese, with baseline BMIs of 64.6 and 66.1. Logistic regression modeling showed a significant association (unadjusted OR ¼ 1.14, 95% CI [1.00, 1.30], P ¼ .05) between BMI and presence of endometrial pathology that grew more statistically significant after adjusting for age and race (adjusted OR ¼ 1.19, 95% CI [1.03–1.36], P ¼ .01), indicating that increasing BMI was associated with greater risk of pathology. Similar relationships with endometrial pathology were present for total fat mass (P ¼ .02), fat percentage (P ¼ .08), and waist circumference (P ¼ .05), suggesting that all measures of obesity explored in the context of this study were associated with increased risk of pathology. Discussion In this sample of morbidly obese women undergoing bariatric surgery, increased BMI was associated with greater risk of endometrial pathology. After adjusting for age and race, every 1-kg/m2 increase in BMI was associated with a 19% increased risk of endometrial pathology. This roughly translates to twofold increased risk of pathology associated with a 5-kg/m2 increase in BMI, a threefold increased risk for a 10-kg/m2 increase in BMI, and a fivefold increased risk for a 20-kg/m2 increase in BMI. Next, 27.6% of bariatric surgery candidates in this sample showed evidence of endometrial hyperplasia, metaplasia, or polyps, suggesting these individuals may require additional clinical follow-up. Although endometrial polyps are generally benign, carrying different prognoses than endometrial hyperplasia or metaplasia, a recent metaanalysis reported that postmenopausal women with polyps
are at higher risk of developing EC [26]. Therefore, clinicians may consider monitoring this condition in highrisk women in the future. Lastly, the rate of pathology in this sample was higher than previously reported for asymptomatic women [20,21] which may indicate that further research is needed in the area of screening for severely obese women. Future research efforts should place specific attention on evaluating the cost-effectiveness of EC screening in high-risk women and identifying characteristics of women who can benefit from screening. Conventionally, BMI is widely used to define obesity because of the difficulties in measuring body fat directly and the inability to evaluate body fat distribution. It has been reported that abdominal fat mass distribution is related to endometrial thickness, whereas the occurrence of EC relates to the amount but not the distribution of adipose tissue [27,28]. One of the strengths of the present study is the ability to look at multiple measures of obesity, including measures of central adiposity, with all of them linked to increased risk of endometrial pathology. Another strength of this study is the focus on younger age groups, including perimenopausal and premenopausal women. Although obesity increases the risk of EC in both premenopausal and postmenopausal women [29], most published studies on endometrial cancer risk factors focus on the postmenopausal population. One quarter of all EC cases occur in premenopausal or perimenopausal women [6]. Although the median age of EC onset in the United States is 62 years, as the number of younger obese women increases, EC may affect younger individuals [30]. This investigation is novel because a general population of severely obese women undergoing bariatric surgery was studied; previous investigations [19,20] studied strictly symptom-free women. The present findings must be considered in the context of the study limitations. First, this subanalysis was restricted to
Endometrial Histology in Severely Obese Women / Surgery for Obesity and Related Diseases ] (2015) 00–00
women with successful biopsies; however, because this group did not statistically significantly differ from those with unsuccessful biopsies, some information bias may have been minimized. Furthermore, even with the small sample, the group was generally representative of the bariatric surgery practice at the authors’ institution and was racially representative of the 2 major ethnic groups in the area. Secondly, because this was part of a pilot investigation, menstrual cycle phase could not be controlled for, due to logistical limitations and the fact that many participants reported irregular cycles. Obese, premenopausal women are likely to have more anovulatory cycles with lower progesterone levels and, thus, are at additional risk for endometrial pathology, which the authors propose to investigate in more detail in future studies. In the future, research studies in this area should focus on developing larger investigations that would be better position to identify the exact relationship between increasing obesity and increased risk of endometrial pathology. Findings of this study have potential screening implications in severely obese women and especially for those who want to preserve fertility. Although hysterectomy is a common treatment for women with hyperplasia, both of the women in the present study who had endometrial hyperplasia were 30–35 years of age and indicated that fertility was still desired. Timely identification of hyperplasia in severely obese women, possibly through innovative screening strategies, and appropriate counseling about conservative versus surgical hyperplasia management might help these women to preserve fertility. These initial findings suggest that obstetrics and gynecology, as well as primary, healthcare providers should pay special attention to the endometrial health of severely obese women, especially those who want to preserve fertility. Conclusions This is one of the first studies to show that, in a sample of female bariatric surgery candidates, increasing obesity was associated with an elevated risk of subclinical endometrial pathology. Future studies must carefully evaluate the link between obesity and endometrial pathology, paying close attention to not only the amount but also the distribution of adipose tissue [27,28]. These findings suggest there may be utility in screening high-risk, obese women for endometrial pathology, although future research with large samples are needed to confirm this hypothesis. Future efforts should also explore changes in endometrial health as a result of weight loss through bariatric surgery, because weight loss may improve or even reverse endometrial hyperplasia [19,20]. In addition to improving understanding of risk factors for endometrial cancer, continuing this line of research may open new avenues for its prevention and control.
5
Disclosures This research was partly funded by the American Cancer Society (MRSG-1—079-01-CPPB), Scaife Foundation at the University of Pittsburgh School of Medicine, and the National Institutes of Health through Grant Numbers UL1 RR024153 and UL1TR000005.
References [1] Bakkum-Gamez JN, Gonzalez-Bosquet J, Laack NN, Mariani A, Dowdy SC. Current issues in the management of endometrial cancer. Mayo Clin Proc 2008;83:97–112. [2] Polednak AP. Trends in incidence rates for obesity-associated cancers in the US. Cancer Detect Prev 2003;27:415–21. [3] Webb PM. Commentary: weight gain, weight loss, and endometrial cancer. Int J Epidemiol 2006;35:166–8. [4] American Cancer Society. Endometrial (uterine) cancer. [updated 2014 Feb 3; cited Accessed 2014 May 15]; Available from: http:// www.cancer.org/cancer/endometrialcancer/detailedguide/endometrialuterine-cancer-what-is-endometrial-cancer. [5] Schouten LJ, Goldbohm RA, van den Brandt PA. Anthropometry, physical activity, and endometrial cancer risk: results from the Netherlands Cohort Study. J Natl Cancer Inst 2004;96:1635–8. [6] Fader AN, Arriba LN, Frasure HE, von Gruenigen VE. Endometrial cancer and obesity: epidemiology, biomarkers, prevention and survivorship. Gynecol Oncol 2009;114:121–7. [7] Pavelka JC, Ben-Shachar I, Fowler JM, et al. Morbid obesity and endometrial cancer: surgical, clinical, and pathologic outcomes in surgically managed patients. Gynecol Oncol 2004;95:588–92. [8] Ward KK, Roncancio AM, Shah NR, et al. The risk of uterine malignancy is linearly associated with body mass index in a cohort of US women. Am J Obstet Gynecol 2013;209:e1–5. [9] Crosbie EJ, Zwahlen M, Kitchener HC, Egger M, Renehan AG. Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2010;19: 3119–30. [10] Daud S, Jalil SS, Griffin M, Ewies AA. Endometrial hyperplasia—the dilemma of management remains: a retrospective observational study of 280 women. Eur J Obstet Gynecol Reprod Biol 2011;159:172–5. [11] Linkov F, Edwards R, Balk J, et al. Endometrial hyperplasia, endometrial cancer and prevention: gaps in existing research of modifiable risk factors. Eur J Cancer 2008;44:1632–44. [12] Epplein M, Reed SD, Voigt LF, Newton KM, Holt VL, Weiss NS. Risk of complex and atypical endometrial hyperplasia in relation to anthropometric measures and reproductive history. Am J Epidemiol 2008;168:563–70. [13] Lacey JV Jr, Chia VM. Endometrial hyperplasia and the risk of progression to carcinoma. Maturitas 2009;63:39–44. [14] Ben-Arie A, Goldchmit C, Laviv Y, et al. The malignant potential of endometrial polyps. Eur J Obstet Gynecol Reprod Biol 2004;115: 206–10. [15] Andersen WA, Taylor PT Jr., Fechner RE, Pinkerton JA. Endometrial metaplasia associated with endometrial adenocarcinoma. Am J Obstet Gynecol 1987;157:597–604. [16] Leng X, Wang M, Zhang SL, Wang D, Cao W, Yang XH. Different methods for the diagnosis of endometrial histological comparative study [article in Chinese]. Zhonghua Fu Chan Ke Za Zhi 2013;48: 891–5. [17] Abdelazim IA, Aboelezz A, Abdulkareem AF. Pipelle endometrial sampling versus conventional dilatation & curettage in patients with abnormal uterine bleeding. J Turk Ger Gynecol Assoc 2013;14:1–5.
6
A. Kaiyrlykyzy et al. / Surgery for Obesity and Related Diseases ] (2015) 00–00
[18] Kazandi M, Okmen F, Ergenoglu AM, et al. Comparison of the success of histopathological diagnosis with dilatation-curettage and Pipelle endometrial sampling. J Obstet Gynaecol 2012;32:790–4. [19] Argenta P, Svendsen C, Elishaev E, et al. Hormone receptor expression patterns in the endometrium of asymptomatic morbidly obese women before and after bariatric surgery. Gynecol Oncol 2014;133:78–82. [20] Argenta PA, Kassing M, Truskinovsky AM, Svendsen CA. Bariatric surgery and endometrial pathology in asymptomatic morbidly obese women: a prospective, pilot study. BJOG 2013;120:795–800. [21] Viola AS, Gouveia D, Andrade L, Aldrighi JM, Viola CF, Bahamondes L. Prevalence of endometrial cancer and hyperplasia in nonsymptomatic overweight and obese women. Aust N Z J Obstet Gynaecol 2008;48:207–13. [22] Gosman GG, King WC, Schrope B, et al. Reproductive health of women electing bariatric surgery. Fertil Steril 2010;94:1426–31. [23] Burke LE, Choo J, Music E, et al. PREFER study: a randomized clinical trial testing treatment preference and two dietary options in behavioral weight management—rationale, design and baseline characteristics. Contemp Clin Trials 2006;27:34–48.
[24] Burke LE, Styn MA, Glanz K, et al. SMART trial: a randomized clinical trial of self-monitoring in behavioral weight managementdesign and baseline findings. Contemp Clin Trials 2009;30:540–51. [25] SAS 9.1.3 [computer program]. Cary, NC: SAS Institute Inc.; 2000– 2004. [26] Lee SC, Kaunitz AM, Sanchez-Ramos L, Rhatigan RM. The oncogenic potential of endometrial polyps: a systematic review and meta-analysis. Obstet Gynecol 2010;116:1197–205. [27] Warming L, Ravn P, Christiansen C. Visceral fat is more important than peripheral fat for endometrial thickness and bone mass in healthy postmenopausal women. Am J Obstet Gynecol 2003;188:349–53. [28] Folsom AR, Kaye SA, Potter JD, Prineas RJ. Association of incident carcinoma of the endometrium with body weight and fat distribution in older women: early findings of the Iowa Women's Health Study. Cancer Res 1989;49:6828–31. [29] Caserta D, Bordi G, Scarani S, Moscarini M. Endometrial adenocarcinoma in a young woman. Eur J Gyneacol Oncol 2013;34: 179–82. [30] Barlin JN, Zhou Q, St. Clair CM, et al. Classification and regression tree (CART) analysis of endometrial carcinoma: seeing the forest for the trees. Gynecol Oncol 2013;130:452–6.
Original article
Endometrial histology in severely obese bariatric surgery candidates: an exploratory analysis Aiym Kaiyrlykyzy, M.D.a, Kyle E. Freese, M.P.H.b,c, Esther Elishaev, M.D.d, Dana H. Bovbjerg, Ph.D.e, Ramesh Ramanathan, M.D.f, Giselle G. Hamad, M.D.f, Carol McCloskey, M.D.f, Andrew D. Althouse, Ph.D.c, Marilyn Huang, M.D., M.S.c, Robert P. Edwards, M.D.c, Faina Linkov, Ph.D.b,c,* a Center for Life Sciences, Nazarbayev University, Astana, Kazakhstan Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA c Department of Obstetrics, Gynecology & Reproductive Sciences, Magee-Womens Research Institute, Pittsburgh, PA d Department of Pathology, Magee-Womens Hospital, Pittsburgh, PA e University of Pittsburgh Cancer Institute, Pittsburgh, PA f Division of General Surgery, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA Received July 28, 2014; accepted December 12, 2014 b
Abstract
Background: Endometrial pathology risk has been linked to obesity; however, little is known of its prevalence in severely obese women not seeking care for endometrial pathology associated symptoms. This pilot study was designed to explore the frequency and risk factors associated with endometrial pathology in cancer-free, severely obese, bariatric surgery candidates using the Pipelle endometrial sampling technique (SureFlex Preferred Curette, Bioteque America, Inc, New Taipei City, Taiwan). Methods: Twenty-nine severely obese bariatric surgery candidates with intact uteruses and no history of endometrial cancer or endometrial ablation were included in this subanalysis from a larger cohort of 47. Endometrial samples were obtained using a Pipelle endometrial suction curette at a single time point before surgery. Logistic regression was used to assess the relationship between body mass index and endometrial pathology when adjusting for age and race. Results: Of the 29 successful biopsies, 8 (27.6%) were classified as abnormal endometrium: 1 was classified as complex atypical hyperplasia, 1 was classified as hyperplasia without atypia, 4 samples were identified with endometrial polyps, and 2 samples were identified with metaplasia. None presented with cancer. Increasing body mass index was significantly associated with higher risk of abnormal endometrium (OR ¼ 1.19, 95% CI [1.03–1.36], P ¼ .01). Conclusions: The findings in this sample suggest that obesity may be associated with increased risk of having undiagnosed endometrial pathology. More thorough examination of relationships between levels of obesity and endometrial pathology are needed to better characterize high cancer risk groups who may benefit from introducing new screening measures. (Surg Obes Relat Dis 2015;]:00–00.) r 2015 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Bariatric surgery; Endometrial cancer; Endometrial hyperplasia; Endometrial polyps; Obesity; Pipelle sampling
This study was funded by the American Cancer Society (MRSG-10-07901-CPPB) and the Scaife Foundation. Biostatistical support was provided by Andrew D. Althouse, Ph.D. * Correspondence: Faina Linkov, Ph.D., M.P.H., Department of Obstetrics, Gynecology & Reproductive Sciences, University of Pittsburgh, 3380 Boulevard of Allies, Room 323, Pittsburgh, PA 15217. E-mail: [email protected]
Endometrial cancer (EC) incidence has been increasing since 2007 and is the most common gynecologic cancer in the United States [1–3]. The American Cancer Society estimates that at least 52,630 new cases of EC will be diagnosed in 2014 [4]. Risk factors for EC, as well as its
http://dx.doi.org/10.1016/j.soard.2014.12.010 1550-7289/r 2015 American Society for Metabolic and Bariatric Surgery. All rights reserved.
2
A. Kaiyrlykyzy et al. / Surgery for Obesity and Related Diseases ] (2015) 00–00
precursor, endometrial hyperplasia (EH), include high levels of unopposed estrogen, low physical activity [5], and obesity [6,7]. A large, retrospective cohort study exploring the association between EC risk and specific body mass index (BMI) found that for every 1 kg/m2 increase in BMI, there was an 11% increase in the likelihood of EC diagnosis [8]. A meta-analysis of BMI and incident EC revealed an overall risk ratio of 1.6 for every 5 units of BMI increase [9]. EH, particularly complex hyperplasia with atypia, is a wellknown precursor for EC [6,10]. Risk factors for EH are similar to those for EC, including increased BMI [11]. Compared with women with normal BMI, previously published work suggests that obese women (BMI 30–39.9) had a 4.6-fold increase in risk of complex hyperplasia (95% CI: 2.1, 10.3) and a 3.7-fold increase in risk of hyperplasia with atypia (95% CI: 1.0, 13.8) [12]. Morbidly obese women (BMI Z40) had a 23-fold increase in risk of complex hyperplasia (95% CI: 6.6, 79.8) and a 13-fold increase in risk of hyperplasia with atypia (95% CI: 1.9, 86.9) [12]. Approximately 30% of women with untreated complex hyperplasia with atypia progress to carcinoma, so timely diagnosis of EH is crucial [13]. In addition to hyperplasia, it is important to know the prevalence of endometrial polyps and metaplasia in the general population of obese women, because those conditions have been associated with EC in previous research [14,15]. Although asymptomatic women generally are not screened for EC, endometrial Pipelle sampling can potentially be used as a routine screening tool in the outpatient setting for identifying endometrial pathologies [16,17]. Because previous literature has shown endometrial Pipelle sampling to be successful in obtaining sufficient tissue [18] and because the sampling can be done on outpatient basis without the use of anesthetics, Pipelle biopsy has been used in this population. In previous studies of untreated, asymptomatic, severely obese women (BMI 435), Argenta et al. found that the prevalence of endometrial hyperplasia is approximately 6.8% [19,20]. Viola et al. found endometrial cancer or hyperplasia in 8.9% of asymptomatic overweight or obese women, both pre -and post- menopausal, undergoing Pipelle biopsy [21]. Although previous studies provided important information on the prevalence of hyperplasia and cancer in asymptomatic women, they did not report information on the prevalence of other pathologies (such as polyps and metaplasia) and they were also limited by the inclusion of asymptomatic women only. The primary objective of the present study was to describe the prevalence of a wide spectrum of endometrial pathologies in a general cohort of cancer-free, severely obese women considering bariatric surgery.
Materials and methods Study participants Severely obese (BMI Z35), female bariatric surgery candidates were recruited from Magee-Women’s Hospital
of the University of Pittsburgh Medical Center Health System (UPMC). Patients were considered eligible to participate in this investigation if they were at least 29 years old (because of a suspected lower prevalence of endometrial pathologies in the younger age group), enrolled in a bariatric surgery program, and expected to undergo bariatric surgery (Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, or sleeve gastrectomy) within 6 months of recruitment. Exclusion criteria included prior endometrial ablation or hysterectomy, severe inflammatory or autoimmune diseases (as these samples were collected from larger study investigating inflammatory biomarkers), or refusal to consent to endometrial biopsy. Patients were not excluded on the basis of gynecologic symptoms such as abnormal menstrual bleeding; however, most patients were asymptomatic. This subanalysis was restricted to women with successful/sufficient endometrial biopsies (biopsies yielding sufficient endometrial tissue for pathology analysis). To justify the focus on participants with successful biopsies, these patients (n ¼ 29) were compared with those without successful biopsies (n ¼ 18) using Wilcoxon tests for continuous variables and χ2 tests for categorical variables to ensure that there was no substantial difference between the groups. All study-related procedures were performed at the Clinical and Translational Research Center of MageeWomen’s Hospital of UPMC by trained clinical and/or research staff. The University of Pittsburgh Institutional Review Board approved this study, and all patients provided written, informed consent (Protocol #PRO08080042).
Measurements Two experienced clinical staff members (a gynecologic oncologist and a physician assistant) obtained endometrial samples using a Pipelle endometrial suction curette in accordance with the manufacturer’s instructions. Cervical ripening agents were not administered before biopsies. Acquired specimens were formalin-fixed, embedded in paraffin, sectioned, and stained using standard hematoxylin and eosin stain preparation, then evaluated by 2 independent pathologists with expertise in gynecologic pathology, who were blinded to the patients’ health histories, age, BMI, and identifying characteristics. A third (senior) pathologist addressed any discrepancies between the findings of the 2 pathologists. Patients who evidenced pathology were referred to a gynecologist or gynecologic oncologist (as appropriate) for follow-up care. A research registered nurse collected anthropometric measurements, during which participants wore light clothing and no shoes. Waist and hip circumferences were measured to the nearest centimeter using a nonstretchable tape. Height was recorded to the nearest inch by a standardized wall-mounted stadiometer. A Tanita body
Endometrial Histology in Severely Obese Women / Surgery for Obesity and Related Diseases ] (2015) 00–00
composition analyzer (Model TBF-310, Tanita Corporation of America [Arlington Heights, IL]) was used to assess weight, total body fat, and percent body fat. Reproductive histories, including gravidity, parity, polycystic ovary syndrome (PCOS), menstrual history, and desired fertility were obtained using a validated reproductive baseline health survey, which has been used previously in large, multicenter studies targeting bariatric surgery patients [22]. Information on co-morbidities was obtained from a general health questionnaire developed and validated by Burke et al. for previously published interventions targeting severely obese individuals [23,24]. Statistical methods Data analysis was performed using SAS Version 9.3 (SAS Institute Inc., Cary, NC) [25]. Descriptive statistics were reported as median (range) for continuous variables and n (%) for categorical variables. The Wilcoxon rank-sum test (continuous variables) and Fisher’s exact test (categorical variables) were used to compare women with identified pathologies (e.g., hyperplasia with atypia, hyperplasia without atypia, metaplasia, or endometrial polyps) with pathology-free women. Differences in race, age, body composition, and other characteristics were evaluated. Logistic regression was used to assess the relationship between BMI and endometrial pathology when adjusting for age and race. P values less than .05 were considered statistically significant. Results Baseline characteristics of the 29 participants with successful biopsies are listed in Table 1. The median age
3
of the patients was 39 (30–62) years, most (68.9%) of whom reported their racial/ethnic background as white, and the median BMI was 46.4 kg/m2 (35.7–66.1). Median gravidity was 2 prior pregnancies, ranging from 0 (never been pregnant) to 12. Thirteen women reported irregular menses and 5 reported being previously diagnosed with PCOS by a healthcare provider. Five women reported a history of hormone use, mainly for contraception, with only one woman reporting prior use of hormone replacement therapy. Common co-morbid conditions reports by participants included hypertension (48%), diabetes (14%), thyroid disease (17%), heart problems (7%), and cancer (7%). Comparison of the 29 participants with successful biopsies to the 18 participants with failed biopsies showed that there were no differences in age (P ¼ .80), race (P ¼ 1.00), BMI (P ¼ .51), waist circumference (P ¼ .62), reproductive history (P ¼ .92), menopausal status (P ¼ .29), regularity of periods (P ¼ .76), or history of hormone use (P ¼ 1.00). The distribution of endometrial histologies is shown in Fig. 1. Eight patients (27.6%, 95% CI [11.3%–43.8%]) had evidence of abnormal endometrium: 2 patients showed evidence of hyperplasia, 2 showed evidence of metaplasia, and 4 had an endometrial polyp. Proliferative pattern was the most common histology (21.6%), and 4 samples revealed a hormonal effect associated with birth control manifested by pseudodecidualized stroma and inactive glands, characteristic of progestin effect. No participants had evidence of EC. Table 1 provides general characteristics of the study population and compares groups by the presence of endometrial pathology. Patients with abnormal endometrium (endometrial hyperplasia with/without atypia or
Table 1 General characteristics of study participants, as well as characteristics stratified by histopathological analysis of endometrial biopsies Characteristic
Successful biopsy (n ¼ 29)
Normal endometrium (n ¼ 21)
Abnormal endometrium (n ¼ 8)
Age (years) Ethnicity White Black Preoperative BMI (kg/m2) Total fat mass (kg) Body fat percentage Waist circumference (cm) Waist-hip ratio Endometrial thickness† Number of prior pregnancies Premenopausal Irregular periods Prior Diagnosis of PCOS History of hormone use
39 (30–62)
38 (31–62)
41 (30–57)
20 (68.9%) 9 (31.1%) 46.4 (35.7–66.1) 67.5 (40.0–107.5) 52.4 (45.3–67.2) 133.9 (106–168) .90 (.79–1.03) 13.0 (2.9–45.6) 2 (0–12) 24 (82.8%) 13 (44.8%) 5 (17.2%) 5 (17.2%)
14 (66.7%) 7 (33.3%) 45.0 (35.7–63.9) 62.3 (40.0–99.8) 50.4 (43.4–60.4) 125 (104–167) .90 (.80–.99) 11.4 (8.3–33.5) 2 (0–8) 18 (85.7%) 8 (40.0%) 3 (14.3%) 5 (23.8%)
6 (75%) 2 (25%) 54.9 (44.8–66.1) 79.9 (67.6–107.5) 54.3 (46.7–67.2) 139 (127–155) .90 (.85–1.00) 13.3 (2.9–45.6) 2 (0–12) 6 (75.0%) 5 (62.5%) 2 (25.0%) 0 (0%)
Abbreviations: BMI ¼ body mass index; PCOS ¼ polycystic ovary syndrome. Note: Continuous variables described by medians (ranges); categorical variables described by n (%). * P-values compare those with abnormal endometrium versus those with normal endometrium. † N ¼ 13 for endometrial thickness (10 with normal endometrium, 3 with abnormal endometrium) due to missing data.
P value* .79 1.00
o .01 o .01 .05 .01 .85 1.00 .63 .60 .16 .58 .29
A. Kaiyrlykyzy et al. / Surgery for Obesity and Related Diseases ] (2015) 00–00
4
Fig. 1. Distribution of endometrial biopsy findings among those undergoing endometrial Pipelle sampling in an outpatient setting.
endometrial polyps) had significantly higher preoperative BMIs (45.0 versus 54.9, P o .01), body fat mass (62.3 kg versus 79.9 kg, P o .01), and waist circumference (125 cm versus 139 cm, P ¼ .01). Both patients diagnosed with hyperplasia in this sample were Class 3 obese, with baseline BMIs of 64.6 and 66.1. Logistic regression modeling showed a significant association (unadjusted OR ¼ 1.14, 95% CI [1.00, 1.30], P ¼ .05) between BMI and presence of endometrial pathology that grew more statistically significant after adjusting for age and race (adjusted OR ¼ 1.19, 95% CI [1.03–1.36], P ¼ .01), indicating that increasing BMI was associated with greater risk of pathology. Similar relationships with endometrial pathology were present for total fat mass (P ¼ .02), fat percentage (P ¼ .08), and waist circumference (P ¼ .05), suggesting that all measures of obesity explored in the context of this study were associated with increased risk of pathology. Discussion In this sample of morbidly obese women undergoing bariatric surgery, increased BMI was associated with greater risk of endometrial pathology. After adjusting for age and race, every 1-kg/m2 increase in BMI was associated with a 19% increased risk of endometrial pathology. This roughly translates to twofold increased risk of pathology associated with a 5-kg/m2 increase in BMI, a threefold increased risk for a 10-kg/m2 increase in BMI, and a fivefold increased risk for a 20-kg/m2 increase in BMI. Next, 27.6% of bariatric surgery candidates in this sample showed evidence of endometrial hyperplasia, metaplasia, or polyps, suggesting these individuals may require additional clinical follow-up. Although endometrial polyps are generally benign, carrying different prognoses than endometrial hyperplasia or metaplasia, a recent metaanalysis reported that postmenopausal women with polyps
are at higher risk of developing EC [26]. Therefore, clinicians may consider monitoring this condition in highrisk women in the future. Lastly, the rate of pathology in this sample was higher than previously reported for asymptomatic women [20,21] which may indicate that further research is needed in the area of screening for severely obese women. Future research efforts should place specific attention on evaluating the cost-effectiveness of EC screening in high-risk women and identifying characteristics of women who can benefit from screening. Conventionally, BMI is widely used to define obesity because of the difficulties in measuring body fat directly and the inability to evaluate body fat distribution. It has been reported that abdominal fat mass distribution is related to endometrial thickness, whereas the occurrence of EC relates to the amount but not the distribution of adipose tissue [27,28]. One of the strengths of the present study is the ability to look at multiple measures of obesity, including measures of central adiposity, with all of them linked to increased risk of endometrial pathology. Another strength of this study is the focus on younger age groups, including perimenopausal and premenopausal women. Although obesity increases the risk of EC in both premenopausal and postmenopausal women [29], most published studies on endometrial cancer risk factors focus on the postmenopausal population. One quarter of all EC cases occur in premenopausal or perimenopausal women [6]. Although the median age of EC onset in the United States is 62 years, as the number of younger obese women increases, EC may affect younger individuals [30]. This investigation is novel because a general population of severely obese women undergoing bariatric surgery was studied; previous investigations [19,20] studied strictly symptom-free women. The present findings must be considered in the context of the study limitations. First, this subanalysis was restricted to
Endometrial Histology in Severely Obese Women / Surgery for Obesity and Related Diseases ] (2015) 00–00
women with successful biopsies; however, because this group did not statistically significantly differ from those with unsuccessful biopsies, some information bias may have been minimized. Furthermore, even with the small sample, the group was generally representative of the bariatric surgery practice at the authors’ institution and was racially representative of the 2 major ethnic groups in the area. Secondly, because this was part of a pilot investigation, menstrual cycle phase could not be controlled for, due to logistical limitations and the fact that many participants reported irregular cycles. Obese, premenopausal women are likely to have more anovulatory cycles with lower progesterone levels and, thus, are at additional risk for endometrial pathology, which the authors propose to investigate in more detail in future studies. In the future, research studies in this area should focus on developing larger investigations that would be better position to identify the exact relationship between increasing obesity and increased risk of endometrial pathology. Findings of this study have potential screening implications in severely obese women and especially for those who want to preserve fertility. Although hysterectomy is a common treatment for women with hyperplasia, both of the women in the present study who had endometrial hyperplasia were 30–35 years of age and indicated that fertility was still desired. Timely identification of hyperplasia in severely obese women, possibly through innovative screening strategies, and appropriate counseling about conservative versus surgical hyperplasia management might help these women to preserve fertility. These initial findings suggest that obstetrics and gynecology, as well as primary, healthcare providers should pay special attention to the endometrial health of severely obese women, especially those who want to preserve fertility. Conclusions This is one of the first studies to show that, in a sample of female bariatric surgery candidates, increasing obesity was associated with an elevated risk of subclinical endometrial pathology. Future studies must carefully evaluate the link between obesity and endometrial pathology, paying close attention to not only the amount but also the distribution of adipose tissue [27,28]. These findings suggest there may be utility in screening high-risk, obese women for endometrial pathology, although future research with large samples are needed to confirm this hypothesis. Future efforts should also explore changes in endometrial health as a result of weight loss through bariatric surgery, because weight loss may improve or even reverse endometrial hyperplasia [19,20]. In addition to improving understanding of risk factors for endometrial cancer, continuing this line of research may open new avenues for its prevention and control.
5
Disclosures This research was partly funded by the American Cancer Society (MRSG-1—079-01-CPPB), Scaife Foundation at the University of Pittsburgh School of Medicine, and the National Institutes of Health through Grant Numbers UL1 RR024153 and UL1TR000005.
References [1] Bakkum-Gamez JN, Gonzalez-Bosquet J, Laack NN, Mariani A, Dowdy SC. Current issues in the management of endometrial cancer. Mayo Clin Proc 2008;83:97–112. [2] Polednak AP. Trends in incidence rates for obesity-associated cancers in the US. Cancer Detect Prev 2003;27:415–21. [3] Webb PM. Commentary: weight gain, weight loss, and endometrial cancer. Int J Epidemiol 2006;35:166–8. [4] American Cancer Society. Endometrial (uterine) cancer. [updated 2014 Feb 3; cited Accessed 2014 May 15]; Available from: http:// www.cancer.org/cancer/endometrialcancer/detailedguide/endometrialuterine-cancer-what-is-endometrial-cancer. [5] Schouten LJ, Goldbohm RA, van den Brandt PA. Anthropometry, physical activity, and endometrial cancer risk: results from the Netherlands Cohort Study. J Natl Cancer Inst 2004;96:1635–8. [6] Fader AN, Arriba LN, Frasure HE, von Gruenigen VE. Endometrial cancer and obesity: epidemiology, biomarkers, prevention and survivorship. Gynecol Oncol 2009;114:121–7. [7] Pavelka JC, Ben-Shachar I, Fowler JM, et al. Morbid obesity and endometrial cancer: surgical, clinical, and pathologic outcomes in surgically managed patients. Gynecol Oncol 2004;95:588–92. [8] Ward KK, Roncancio AM, Shah NR, et al. The risk of uterine malignancy is linearly associated with body mass index in a cohort of US women. Am J Obstet Gynecol 2013;209:e1–5. [9] Crosbie EJ, Zwahlen M, Kitchener HC, Egger M, Renehan AG. Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2010;19: 3119–30. [10] Daud S, Jalil SS, Griffin M, Ewies AA. Endometrial hyperplasia—the dilemma of management remains: a retrospective observational study of 280 women. Eur J Obstet Gynecol Reprod Biol 2011;159:172–5. [11] Linkov F, Edwards R, Balk J, et al. Endometrial hyperplasia, endometrial cancer and prevention: gaps in existing research of modifiable risk factors. Eur J Cancer 2008;44:1632–44. [12] Epplein M, Reed SD, Voigt LF, Newton KM, Holt VL, Weiss NS. Risk of complex and atypical endometrial hyperplasia in relation to anthropometric measures and reproductive history. Am J Epidemiol 2008;168:563–70. [13] Lacey JV Jr, Chia VM. Endometrial hyperplasia and the risk of progression to carcinoma. Maturitas 2009;63:39–44. [14] Ben-Arie A, Goldchmit C, Laviv Y, et al. The malignant potential of endometrial polyps. Eur J Obstet Gynecol Reprod Biol 2004;115: 206–10. [15] Andersen WA, Taylor PT Jr., Fechner RE, Pinkerton JA. Endometrial metaplasia associated with endometrial adenocarcinoma. Am J Obstet Gynecol 1987;157:597–604. [16] Leng X, Wang M, Zhang SL, Wang D, Cao W, Yang XH. Different methods for the diagnosis of endometrial histological comparative study [article in Chinese]. Zhonghua Fu Chan Ke Za Zhi 2013;48: 891–5. [17] Abdelazim IA, Aboelezz A, Abdulkareem AF. Pipelle endometrial sampling versus conventional dilatation & curettage in patients with abnormal uterine bleeding. J Turk Ger Gynecol Assoc 2013;14:1–5.
6
A. Kaiyrlykyzy et al. / Surgery for Obesity and Related Diseases ] (2015) 00–00
[18] Kazandi M, Okmen F, Ergenoglu AM, et al. Comparison of the success of histopathological diagnosis with dilatation-curettage and Pipelle endometrial sampling. J Obstet Gynaecol 2012;32:790–4. [19] Argenta P, Svendsen C, Elishaev E, et al. Hormone receptor expression patterns in the endometrium of asymptomatic morbidly obese women before and after bariatric surgery. Gynecol Oncol 2014;133:78–82. [20] Argenta PA, Kassing M, Truskinovsky AM, Svendsen CA. Bariatric surgery and endometrial pathology in asymptomatic morbidly obese women: a prospective, pilot study. BJOG 2013;120:795–800. [21] Viola AS, Gouveia D, Andrade L, Aldrighi JM, Viola CF, Bahamondes L. Prevalence of endometrial cancer and hyperplasia in nonsymptomatic overweight and obese women. Aust N Z J Obstet Gynaecol 2008;48:207–13. [22] Gosman GG, King WC, Schrope B, et al. Reproductive health of women electing bariatric surgery. Fertil Steril 2010;94:1426–31. [23] Burke LE, Choo J, Music E, et al. PREFER study: a randomized clinical trial testing treatment preference and two dietary options in behavioral weight management—rationale, design and baseline characteristics. Contemp Clin Trials 2006;27:34–48.
[24] Burke LE, Styn MA, Glanz K, et al. SMART trial: a randomized clinical trial of self-monitoring in behavioral weight managementdesign and baseline findings. Contemp Clin Trials 2009;30:540–51. [25] SAS 9.1.3 [computer program]. Cary, NC: SAS Institute Inc.; 2000– 2004. [26] Lee SC, Kaunitz AM, Sanchez-Ramos L, Rhatigan RM. The oncogenic potential of endometrial polyps: a systematic review and meta-analysis. Obstet Gynecol 2010;116:1197–205. [27] Warming L, Ravn P, Christiansen C. Visceral fat is more important than peripheral fat for endometrial thickness and bone mass in healthy postmenopausal women. Am J Obstet Gynecol 2003;188:349–53. [28] Folsom AR, Kaye SA, Potter JD, Prineas RJ. Association of incident carcinoma of the endometrium with body weight and fat distribution in older women: early findings of the Iowa Women's Health Study. Cancer Res 1989;49:6828–31. [29] Caserta D, Bordi G, Scarani S, Moscarini M. Endometrial adenocarcinoma in a young woman. Eur J Gyneacol Oncol 2013;34: 179–82. [30] Barlin JN, Zhou Q, St. Clair CM, et al. Classification and regression tree (CART) analysis of endometrial carcinoma: seeing the forest for the trees. Gynecol Oncol 2013;130:452–6.