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Body Mass Index, Hormone Replacement Therapy, and Endometrial Cancer Risk: A Meta-Analysis
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Abstract
Background: Body mass index (BMI) is a risk factor for endometrial cancer. We quantified the risk and investigated whether the association differed by use of hormone replacement therapy (HRT), menopausal status, and histologic type. Methods: We searched MEDLINE and EMBASE (1966 to December 2009) to identify prospective studies of BMI and incident endometrial cancer. We did random-effects meta-analyses, meta-regressions, and generalized least square regressions for trend estimations assuming linear, and piecewise linear, relationships. Results: Twenty-four studies (17,710 cases) were analyzed; 9 studies contributed to analyses by HRT, menopausal status, or histologic type, all published since 2003. In the linear model, the overall risk ratio (RR) per 5 kg/m2 increase in BMI was 1.60 (95% CI, 1.52–1.68), P < 0.0001. In the piecewise model, RRs compared with a normal BMI were 1.22 (1.19–1.24), 2.09 (1.94–2.26), 4.36 (3.75–5.10), and 9.11 (7.26–11.51) for BMIs of 27, 32, 37, and 42 kg/m2, respectively. The association was stronger in never HRT users than in ever users: RRs were 1.90 (1.57–2.31) and 1.18 (95% CI, 1.06–1.31) with P for interaction = 0.003. In the piecewise model, the RR in never users was 20.70 (8.28–51.84) at BMI 42 kg/m2, compared with never users at normal BMI. The association was not affected by menopausal status (P = 0.34) or histologic type (P = 0.26). Conclusions: HRT use modifies the BMI-endometrial cancer risk association. Impact: These findings support the hypothesis that hyperestrogenia is an important mechanism underlying the BMI-endometrial cancer association, whilst the presence of residual risk in HRT users points to the role of additional systems. Cancer Epidemiol Biomarkers Prev; 19(12); 3119–30. ©2010 AACR.
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“Established risk factors for development of EC include obesity and the presence of premalignant lesions associated with endometrial hyperplasia [75,76], with oestrogen exposure considered a key driver of both endometrial hyperplasia and Type I EC that make up 75% of EC cases [76].”
From Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders (2018) · cites this paper as [75]
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“Thus, the BMI-based dose-response meta-analyses were equivalent to suggesting an increase in risk by 4%, 28%, and 4%, per 5 kg of weight gain for postmenopausal BC, EC among HRT nonusers, and OC among HRT nonusers, respectively (6,9,14).”
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BackgroundAssociation of the Age at Menarche with Site-Specific Cancer Risks in Pooled Data from Nine Cohorts
Fuhrman, B. J., Moore, S. C., Byrne, C., Makhoul, I., Kitahara, C. M., de González, A. B., Linet, M. S., Weiderpass, E., Adami, H., Freedman, N. D., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-19-3093 · Cited by 80
“This pattern echoes that observed for BMI, which is known to be more strongly associated with endometrial cancer risk among never hormone users than current users (46).”
BackgroundResultLuhn, P., Dallal, C. M., Weiss, J. M., Black, A., Huang, W., Lacey, J. V., Hayes, R. B., Stanczyk, F. Z., Wentzensen, N., & Brinton, L. A. (2013) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-13-0258 · Cited by 78
“The effect of BMI on endometrial cancer risk is restricted to women who have not used MHT (34) and conversely,”
Excess adiposity and survival in patients with colorectal cancer: a systematic review
Parkin, E., O'Reilly, D. A., Sherlock, D., Manoharan, P., & Renehan, A. G. (2014) · Obesity Reviews · doi:10.1111/obr.12140 · Cited by 77
“Statistical modelling We performed dose-response meta-analyses where risk was reported for three or more BMI categories per study, as we have described elsewhere (3,8,34).”
BackgroundMethodSelf-citationMcElroy, J. A., Kruse, R. L., Guthrie, J. M., Gangnon, R. E., & Robertson, J. D. (2017) · PLoS ONE · doi:10.1371/journal.pone.0179360 · Cited by 72
Body mass index and mortality in patients with gastric cancer: a large cohort study
Lee, J. H., Park, B., Joo, J., Kook, M., Kim, Y., Lee, J. Y., Kim, C. G., Choi, I. J., Eom, B. W., Yoon, H. M., et al. (2018) · Gastric Cancer · doi:10.1007/s10120-018-0818-x · Cited by 73
“Endometrial cancer, for example, has been strongly associated with an increased body mass index (BMI) [4].”
BackgroundIs estrogen plus progestin menopausal hormone therapy safe with respect to endometrial cancer risk?
Trabert, B. L., Wentzensen, N., Yang, H., Sherman, M. E., Hollenbeck, A. R., Park, Y., & Brinton, L. A. (2012) · International Journal of Cancer · doi:10.1002/ijc.27623 · Cited by 71
Endometrial cancer prevention in high-risk women
Njoku, K., Abiola, J., Russell, J., & Crosbie, E. J. (2019) · Best Practice & Research Clinical Obstetrics & Gynaecology · doi:10.1016/j.bpobgyn.2019.12.005 · Cited by 68
Self-citationAssociation between Five Lifestyle Habits and Cancer Risk: Results from the E3N Cohort
Dartois, L., Fagherazzi, G., Boutron‐Ruault, M., Mesrine, S., & Clavel‐Chapelon, F. (2014) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-13-0325 · Cited by 69
“was associated with a decreased risk of endometrial cancer (47).”
BackgroundEndometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders
Gibson, D. A., Simitsidellis, I., Collins, F., & Saunders, P. T. K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103276 · Cited by 70
“Established risk factors for development of EC include obesity and the presence of premalignant lesions associated with endometrial hyperplasia [75,76], with oestrogen exposure considered a key driver of both endometrial hyperplasia and Type I EC that make up 75% of EC cases [76].”
BackgroundYasin, H. K., Taylor, A. H., & Ayakannu, T. (2021) · Cancers · doi:10.3390/cancers13092149 · Cited by 65
“These data need to be examined in detail, since menopausal status and histological subtypes had no bearing on the relative risk calculations [58].”
BackgroundInfluentialFrom Staging to Prognostication
Nougaret, S., Lakhman, Y., Vargas, H. A., Colombo, P. E., Fujii, S., Reinhold, C., & Sala, E. (2017) · Magnetic Resonance Imaging Clinics of North America · doi:10.1016/j.mric.2017.03.010 · Cited by 62
Huang, C., Chen, C., Chen, Y., Chiang, C., Hsu, T., Lin, M.-C., Lai, M., Chen, C., You, S., & Cheng, W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051372 · Cited by 57
Barr, C. E., Ryan, N. A. J., Derbyshire, A. E., Wan, Y.-L. L., MacKintosh, M. L., McVey, R. J., Bolton, J., Fitzgerald, C. T., Awad, D., Slade, R. J., et al. (2021) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-21-0229 · Cited by 55
“It has been estimated that every 5 kg/m(2) increase in body mass index (BMI) confers a 60% higher lifetime risk of endometrial cancer (2), such that women with a BMI > 40 kg/m(2) are seven times more likely to develop endometrial cancer than normal-weight women (3).”
BackgroundSelf-citationMetabolomic Biomarkers for Detection, Prognosis and Identifying Recurrence in Endometrial Cancer
Njoku, K., Sutton, C. J. J., Whetton, A. D., & Crosbie, E. J. (2020) · Metabolites · doi:10.3390/metabo10080314 · Cited by 55
“Of these, obesity is the most consistently cited risk factor and is strongly related to EC, with every 5 unit increase in BMI leading to a 60% increased risk of the disease [32].”
BackgroundSelf-citationTemkin, S. M., Minasian, L. M., & Noone, A. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00089 · Cited by 53
Kitson, S., Lindsay, J., Sivalingam, V. N., Lunt, M., Ryan, N. A. J., Edmondson, R. J., Rutter, M. K., & Crosbie, E. J. (2017) · Gynecologic Oncology · doi:10.1016/j.ygyno.2017.11.019 · Cited by 53
Self-citationObesity, inflammation, and cancer in dogs: Review and perspectives
Marchi, P. H., Vendramini, T. H. A., Perini, M. P., Zafalon, R. V. A., Amaral, A. R., Ochamotto, V. A., da Silveira, J. C., Dagli, M. L., & Brunetto, M. A. (2022) · Frontiers in Veterinary Science · doi:10.3389/fvets.2022.1004122 · Cited by 69
Brenner, D. R. (2014) · Preventive Medicine · doi:10.1016/j.ypmed.2014.06.018 · Cited by 49
YAP/TAZ regulates the insulin signaling via IRS1/2 in endometrial cancer.
Wang, C., Jeong, K., Jiang, H., Guo, W., Gu, C., Lu, Y., & Liang, J. (2016) · PubMed Central · Cited by 50
Monocarboxylate Transporter 1 (MCT1) is an independent prognostic biomarker in endometrial cancer
Latif, A., Chadwick, A. L., Kitson, S., Gregson, H. J., Sivalingam, V. N., Bolton, J., McVey, R. J., Roberts, S. A., Marshall, K. M., Williams, K. J., et al. (2017) · BMC Clinical Pathology · doi:10.1186/s12907-017-0067-7 · Cited by 50
Self-citationTen-Year Comparison Study of Type 1 and 2 Endometrial Cancers: Risk Factors and Outcomes
Feinberg, J., Albright, B. B., Black, J., Lu, L., Passarelli, R., Gysler, S. M., Whicker, M. E., Altwerger, G. H., Menderes, G., Hui, P., et al. (2019) · Gynecologic and Obstetric Investigation · doi:10.1159/000493132 · Cited by 50
The impact of obesity and bariatric surgery on the immune microenvironment of the endometrium
Naqvi, A., MacKintosh, M. L., Derbyshire, A. E., Tsakiroglou, A. M., Walker, T. D. J., McVey, R. J., Bolton, J., Fergie, M., Bagley, S., Ashton, G., et al. (2021) · International Journal of Obesity · doi:10.1038/s41366-021-01027-6 · Cited by 49
Self-citationObesity and female malignancies
Benedetto, C., Salvagno, F., Canuto, E. M., & Gennarelli, G. (2015) · Best Practice & Research Clinical Obstetrics & Gynaecology · doi:10.1016/j.bpobgyn.2015.01.003 · Cited by 49
Detecting Endometrial Cancer by Blood Spectroscopy: A Diagnostic Cross-Sectional Study
Paraskevaidi, M., Morais, C. L. M., Ashton, K. M., Stringfellow, H. F., McVey, R. J., Ryan, N. A. J., O’Flynn, H., Sivalingam, V. N., Kitson, S., MacKintosh, M. L., et al. (2020) · Cancers · doi:10.3390/cancers12051256 · Cited by 48
“Replication of our results in even larger cohorts and in high risk groups, such as women with significant obesity [41], and those with inherited predisposition syndromes, for example Lynch syndrome [42], is an important consideration for the future validation of spectroscopy for endometrial cancer detection.”
ResultSelf-citationPsaltopoulou, T., Sergentanis, T. N., Ntanasis‐Stathopoulos, I., Tzanninis, I., Riza, E., & Dimopoulos, M. A. (2019) · International Journal of Cancer · doi:10.1002/ijc.32109 · Cited by 47
Study, O. B. O. T. M. W., Yang, T., Cairns, B. J., Allen, N. E., Sweetland, S., REEVES, G. K., & Beral, V. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.229 · Cited by 45
“This is consistent with a meta-analysis that demonstrated a stronger association between BMI and endometrial cancer risk among postmenopausal women compared with premenopausal women, and among never users of hormone therapy for menopause compared with ever users (Crosbie et al, 2010).”
BackgroundResultInfluentialDring, J. C., Forma, A., Chilimoniuk, Z., Dobosz, M., Teresiński, G., Buszewicz, G., Flieger, J., Cywka, T., Januszewski, J., & Baj, J. (2021) · Nutrients · doi:10.3390/nu14010185 · Cited by 45
“Obesity is the major risk factor for the development of endometrial cancer considering both its high rates and physical inactivity in high-income countries [62].”
BackgroundAn aggregated analysis of hormonal factors and endometrial cancer risk by parity
Schonfeld, S. J., Hartge, P. A., Pfeiffer, R. M., Freedman, D. M., Greenlee, R. T., Linet, M. S., Park, Y., Schairer, C., Visvanathan, K., & Lacey, J. V. (2012) · Cancer · doi:10.1002/cncr.27909 · Cited by 43
“Models assessing body mass index (BMI) were stratified by MHT, and vice versa, based on previously reported interactions between these exposures.(18-21) To estimate the joint associations between nulliparity and BMI, OCs, and MHT, we fit models that included all women (nulliparous and parous) and used parous women in…”
MethodHormone Replacement Therapy in Females Can Decrease the Risk of Lung Cancer: A Meta-Analysis
Yao, Y., Gu, X., Zhu, J., Yuan, D., & Song, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071236 · Cited by 43
The levels of the sex hormones are not different between type 1 and type 2 endometrial cancer
Wan, J., Gao, Y., Zeng, K., Yin, Y., Zhao, M., Wei, J., & Chen, Q. (2016) · Scientific Reports · doi:10.1038/srep39744 · Cited by 42
Wang, L., Du, Z., Qiao, J., & Gao, S. (2020) · Aging · doi:10.18632/aging.103247 · Cited by 46
Executive Summary of the Uterine Cancer Evidence Review Conference
Chelmow, D., Brooks, R., Cavens, A., Huber-Keener, K. J., Scott, D. M., Sheth, S. S., Whetstone, S., Worly, B., & Burke, W. (2022) · Obstetrics and Gynecology · doi:10.1097/aog.0000000000004711 · Cited by 43
Endometrial cancer and obesity
Kitson, S., & Crosbie, E. J. (2019) · The Obstetrician & Gynaecologist · doi:10.1111/tog.12601 · Cited by 39
Self-citationJarząbek, K., Koda, M., Walentowicz‐Sadlecka, M., Grabiec, M., Laudański, P., & Wołczyński, S. (2013) · Tumor Biology · doi:10.1007/s13277-013-0991-9 · Cited by 38
“BMI is an unquestionable risk factor of endometrial cancer [21, 22].”
BackgroundEvaluation of risk factors for complications after bariatric surgery
Quilliot, D., Sirveaux, M.-A., Nominé-Criqui, C., Fouquet, T., Reibel, N., & Brunaud, L. (2018) · Journal of Visceral Surgery · doi:10.1016/j.jviscsurg.2018.01.004 · Cited by 38
Obesity as a tumour development triggering factor
Budny, A., Grochowski, C., Kozłowski, P., Kolak, A., Kamińska, M., Kukiełka-Budny, B., Abramiuk, M., & Burdan, F. (2019) · Annals of Agricultural and Environmental Medicine · doi:10.26444/aaem/100664 · Cited by 38
Amankwah, E. K., Friedenreich, C. M., Magliocco, A. M., Brant, R., Courneya, K. S., Speidel, T., Rahman, W., Langley, A. R., & Cook, L. S. (2013) · American Journal of Epidemiology · doi:10.1093/aje/kws434 · Cited by 35
Metabolomic Biomarkers for the Detection of Obesity-Driven Endometrial Cancer
Njoku, K., Campbell, A. E., Geary, B., MacKintosh, M. L., Derbyshire, A. E., Kitson, S., Sivalingam, V. N., Pierce, A., Whetton, A. D., & Crosbie, E. J. (2021) · Cancers · doi:10.3390/cancers13040718 · Cited by 35
“Obesity is the major risk factor for type I cancers of low-grade endometrioid morphology, with every 5 kg/m2 increase in body mass index (BMI) linked to a 60% increased cancer risk [2].”
BackgroundSelf-citationCigarette Smoking and Estrogen-Related Cancer
Baron, J. A., Nichols, H. B., Anderson, C., & Safe, S. (2021) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-20-1803 · Cited by 42
Metadata
- Authors
- Crosbie, E. J., Zwahlen, M., Kitchener, H. C., Egger, M., & Renehan, A. G.
- Affiliations
- University of Bern (CH)
- Venue
- Cancer Epidemiology, Biomarkers & Prevention
- Published
- 2010-12-01
- Volume
- 19
- Issue
- 12
- Pages
- 3119-3130
- ISSN
- 1055-9965 (ISSN-L)
- 1538-7755
- OpenAlex
- W2076975509
- Cited by
- 321
- References
- 85
- Citations by year
- 2026: 21 · 2025: 19 · 2024: 15 · 2023: 24 · 2022: 25 · 2021: 25 · 2020: 26 · 2019: 15 · 2018: 19 · 2017: 20 · 2016: 21 · 2015: 33 · 2014: 23 · 2013: 21 · 2012: 9
- FWCI
- 1.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Epidemiology Biomarkers & Prevention (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- BORIS (University Library Bern) (submittedVersion)
- Funders
- National Institute for Health and Care Research (CL-2007-06-005)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Risks and Factors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
- Keywords
- body mass index, endometrial cancer, hormone replacement therapy, obesity, menopausal status, histological subtypes, cancer risk modification, dose-response relationship, postmenopausal women, endometrial hyperplasia, endometrial adenocarcinoma, endometrioid carcinoma, serous carcinoma
- MeSH terms
- Female, Humans, Risk Factors, Cohort Studies, Body Mass Index, Endometrial Neoplasms, Hormone Replacement Therapy
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