Intrauterine devices and endometrial cancer risk: A pooled analysis of the Epidemiology of Endometrial Cancer Consortium

Intrauterine devices (IUDs), long‐acting and reversible contraceptives, induce a number of immunological and biochemical changes in the uterine environment that could affect endometrial cancer (EC) risk. We addressed this relationship through a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We combined individual‐level data from 4 cohort and 14 case‐control studies, in total 8,801 EC cases and 15,357 controls. Using multivariable logistic regression, we estimated pooled odds ratios (pooled‐ORs) and 95% confidence intervals (CIs) for EC risk associated with ever use, type of device, ages at first and last use, duration of use and time since last use, stratified by study and adjusted for confounders. Ever use of IUDs was inversely related to EC risk (pooled‐OR = 0.81, 95% CI = 0.74–0.90). Compared with never use, reduced risk of EC was observed for inert IUDs (pooled‐OR = 0.69, 95% CI = 0.58–0.82), older age at first use (≥35 years pooled‐OR = 0.53, 95% CI = 0.43–0.67), older age at last use (≥45 years pooled‐OR = 0.60, 95% CI = 0.50–0.72), longer duration of use (≥10 years pooled‐OR = 0.61, 95% CI = 0.52–0.71) and recent use (within 1 year of study entry pooled‐OR = 0.39, 95% CI = 0.30–0.49). Future studies are needed to assess the respective roles of detection biases and biologic effects related to foreign body responses in the endometrium, heavier bleeding (and increased clearance of carcinogenic cells) and localized hormonal changes.

[1]  S. Grénman,et al.  Cancer Risk in Women Using the Levonorgestrel-Releasing Intrauterine System in Finland , 2014, Obstetrics and gynecology.

[2]  M. Pike,et al.  Type I and II endometrial cancers: have they different risk factors? , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  P. Hartge,et al.  An aggregated analysis of hormonal factors and endometrial cancer risk by parity , 2013, Cancer.

[4]  I. Sinai,et al.  Contraceptive failure in the United States. , 2012, Contraception.

[5]  P. Saxena,et al.  Comparison of levonorgestrel and copper releasing intrauterine contraceptive device on body iron stores and menstrual bleeding patterns: experience on Indian women. , 2012, European review for medical and pharmacological sciences.

[6]  A. Mantovani,et al.  Cancer-related inflammation: common themes and therapeutic opportunities. , 2012, Seminars in cancer biology.

[7]  A. Kulczycki,et al.  Revival of the intrauterine device: increased insertions among US women with employer-sponsored insurance, 2002-2008. , 2012, Contraception.

[8]  A. Spurdle,et al.  Use of talcum powder and endometrial cancer risk , 2012, Cancer Causes & Control.

[9]  M. Irwin,et al.  Physical activity and endometrial cancer in a population-based case–control study , 2011, Cancer Causes & Control.

[10]  C. Friedenreich,et al.  Case–control study of lifetime total physical activity and endometrial cancer risk , 2010, Cancer Causes & Control.

[11]  N. Weiss,et al.  Use of nonsteroidal antiinflammatory drugs and risk of endometrial cancer. , 2009, American journal of epidemiology.

[12]  L. Brinton,et al.  Timing of births and endometrial cancer risk in Swedish women , 2009, Cancer Causes & Control.

[13]  Shannon M. Lynch,et al.  Maximizing resources to study an uncommon cancer: E2C2—Epidemiology of Endometrial Cancer Consortium , 2009, Cancer Causes & Control.

[14]  L. Dennis,et al.  Meta-analysis of intrauterine device use and risk of endometrial cancer. , 2008, Annals of epidemiology.

[15]  C. Sima,et al.  Variants in hormone biosynthesis genes and risk of endometrial cancer , 2008, Cancer Causes & Control.

[16]  R. Broaddus,et al.  Prospective determination of prevalence of lynch syndrome in young women with endometrial cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  K. Curtis,et al.  Neoplasia with use of intrauterine devices. , 2007, Contraception.

[18]  H. Critchley,et al.  Endometrial effects of intrauterine levonorgestrel. , 2007, Contraception.

[19]  H. Croxatto,et al.  Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action. , 2007, Contraception.

[20]  M. García-Closas,et al.  Reproductive risk factors for endometrial cancer among Polish women , 2007, British Journal of Cancer.

[21]  X. Shu,et al.  Dietary Folate Intake, MTHFR Genetic Polymorphisms, and the Risk of Endometrial Cancer among Chinese Women , 2007, Cancer Epidemiology Biomarkers & Prevention.

[22]  X. Shu,et al.  Oral contraceptive and IUD use and endometrial cancer: A population‐based case–control study in Shanghai, China , 2006, International journal of cancer.

[23]  H. Checkoway,et al.  Menstrual and reproductive factors in relation to risk of endometrial cancer in Chinese women , 2006, Cancer Causes & Control.

[24]  A. Ørbo,et al.  Effect of levonorgestrel IUD and oral medroxyprogesterone acetate on glandular and stromal progesterone receptors (PRA and PRB), and estrogen receptors (ER-alpha and ER-beta) in human endometrial hyperplasia. , 2006, Gynecologic oncology.

[25]  R. Ness,et al.  Inflammation and Endometrial Cancer: A Hypothesis , 2005, Cancer Epidemiology Biomarkers & Prevention.

[26]  D. Cheng,et al.  Intrauterine devices and reproductive health: American women in feast and famine. , 2004, Contraception.

[27]  K. Mishra,et al.  Evaluation of endometrial steroid receptors and cell mitotic activity in women using copper intrauterine device: Can Cu‐T prevent endometrial cancer? , 2004, The journal of obstetrics and gynaecology research.

[28]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[29]  R. Mikolajczyk,et al.  Mechanisms of action of intrauterine devices: update and estimation of postfertilization effects. , 2002, American journal of obstetrics and gynecology.

[30]  O. Paltiel,et al.  IUD use and the risk of endometrial cancer. , 2002, European journal of obstetrics, gynecology, and reproductive biology.

[31]  Hoda Anton-Culver,et al.  High breast cancer incidence rates among California teachers: results from the California Teachers Study (United States) , 2002, Cancer Causes & Control.

[32]  S. Thompson,et al.  How should meta‐regression analyses be undertaken and interpreted? , 2002, Statistics in medicine.

[33]  M. Thun,et al.  The American Cancer Society Cancer Prevention Study II Nutrition Cohort , 2002, Cancer.

[34]  H. Adami,et al.  Use of oral contraceptives and breast cancer risk: The Norwegian-Swedish Women's Lifestyle and Health Cohort Study. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[35]  J. Freudenheim,et al.  Diet in the epidemiology of endometrial cancer in Western New York (United States) , 2000, Cancer Causes & Control.

[36]  J. Stanford,et al.  Continuous combined hormone replacement therapy and risk of endometrial cancer. , 2000, American journal of obstetrics and gynecology.

[37]  J. Paavonen,et al.  Expression of sex steroid receptors and Ki-67 in the endometria of menorrhagic women: effects of intrauterine levonorgestrel. , 2000, Molecular human reproduction.

[38]  E. Lazcano-Ponce,et al.  Reproductive factors of ovarian and endometrial cancer risk in a high fertility population in Mexico. , 1999, Cancer research.

[39]  L. Xiaoqun,et al.  The effect of a levonorgestrel-releasing intrauterine device on human endometrial oestrogen and progesterone receptors after one year of use , 1999 .

[40]  E. Rutanen,et al.  The effect of intrauterine levonorgestrel use on the expression of c-JUN, oestrogen receptors, progesterone receptors and Ki-67 in human endometrium. , 1998, Molecular human reproduction.

[41]  D. Mishell Intrauterine devices: mechanisms of action, safety, and efficacy. , 1998, Contraception.

[42]  H. Critchley,et al.  Progestin receptor isoforms and prostaglandin dehydrogenase in the endometrium of women using a levonorgestrel-releasing intrauterine system. , 1998, Human reproduction.

[43]  L. Brinton,et al.  Intrauterine device use and endometrial cancer risk. , 1997, International journal of epidemiology.

[44]  M. Thiéry Pioneers of the intrauterine device. , 1997, The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception.

[45]  N. Weiss,et al.  Endometrial cancer in relation to intra‐uterine device use , 1997, International journal of cancer.

[46]  K. Rosenblatt,et al.  Intrauterine devices and endometrial cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. , 1996, Contraception.

[47]  C. la Vecchia,et al.  Intake of selected micronutrients and the risk of endometrial carcinoma , 1996, Cancer.

[48]  I. Milsom,et al.  The influence of the Gyne-T 380S IUD on menstrual blood loss and iron status. , 1995, Contraception.

[49]  B. Xiao,et al.  Effect of levonorgestrel-releasing intrauterine device on hormonal profile and menstrual pattern after long-term use. , 1995, Contraception.

[50]  E. Rutanen,et al.  Effect of intrauterine contraceptive devices on cytokine messenger ribonucleic acid expression in the human endometrium. , 1995, Fertility and sterility.

[51]  J. Palmer,et al.  The Black Women's Health Study: a follow-up study for causes and preventions of illness. , 1995, Journal of the American Medical Women's Association.

[52]  P. Strax,et al.  A prospective study of endogenous estrogens and breast cancer in postmenopausal women. , 1995, Journal of the National Cancer Institute.

[53]  C. la Vecchia,et al.  Intrauterine device use and risk of endometrial cancer. , 1994, British Journal of Cancer.

[54]  W. Thompson,et al.  Intra‐uterine contraception and the risk of endometrial cancer , 1993, International journal of cancer.

[55]  R. Hoover,et al.  Reproductive, menstrual, and medical risk factors for endometrial cancer: results from a case-control study. , 1992, American journal of obstetrics and gynecology.

[56]  J. Fraumeni,et al.  A population‐based case‐control study of endometrial cancer in shanghai, china , 1991, International journal of cancer.

[57]  Thomas Db,et al.  Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. , 1991, International journal of cancer.

[58]  M. Pike,et al.  The dose-effect relationship between 'unopposed' oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. , 1988, British Journal of Cancer.

[59]  A. Andrade,et al.  Quantitative studies on menstrual blood loss in IUD users. , 1987, Contraception.

[60]  E. Shalev,et al.  Serum ovarian steroids, prolactin and prostaglandin metabolites in women using the inert intrauterine device , 1987, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[61]  P. González-Gancedo,et al.  The effect of copper ionsin vivo on specific hormonal endometrial receptors , 1986, Advances in contraception : the official journal of the Society for the Advancement of Contraception.

[62]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[63]  D. Ribatti,et al.  Possible role of mast cells in the mechanism of action of intrauterine contraceptive devices. , 1984, American journal of obstetrics and gynecology.

[64]  T. Luukkainen,et al.  Body iron stores and patterns of bleeding after insertion of a levonorgestrel- or a copper-releasing intrauterine contraceptive device. , 1982, Contraception.

[65]  M. Pike,et al.  Endogenous hormones as a major factor in human cancer. , 1982, Cancer research.

[66]  C. la Vecchia,et al.  Oestrogens and obesity as risk factors for endometrial cancer in Italy. , 1982, International journal of epidemiology.

[67]  P. Ylöstalo,et al.  Endometrial estrogen and progestin receptors in women bearing a progesterone-releasing intrauterine device. , 1980, Contraception.

[68]  R. Snowden Analysis of Intrauterine Contraception. Proceedings of the Third International Conference on Intrauterine Contraception . Edited by Hefnawi F. and S. J. Segal. Pp. 490 + xii. (North-Holland, Amsterdam, 1975.)Price US $32.50. , 1976, Journal of Biosocial Science.

[69]  S. Segal,et al.  Analysis of intrauterine contraception : proceedings of the Third International Conference on Intrauterine Contraception, Cairo, Arab Republic of Egypt, 12-14 December 1974 , 1976 .

[70]  J. Bonnar,et al.  MENSTRUAL BLOOD-LOSS WITH INTRAUTERINE DEVICES , 1976, The Lancet.

[71]  D. Mishell,et al.  Progesterone and Estradiol Patterns in Women Using an Intrauterine Contraceptive Device , 1975, Obstetrics and gynecology.

[72]  Brenner Pf,et al.  Progesterone and estradiol patterns in women using an intrauterine contraceptive device. , 1975 .

[73]  D. Mishell,et al.  Reactions of human endometrium to the intrauterine foreign body. II. Long term effects on the endometrial histology and cytology. , 1971, American journal of obstetrics and gynecology.

[74]  P. Kraft,et al.  Reproductive factors and postmenopausal hormone use in relation to endometrial cancer risk in the Nurses' Health Study cohort 1976–2004 , 2010, International journal of cancer.

[75]  P. Crosignani Intrauterine devices and intrauterine systems. , 2008, Human reproduction update.

[76]  J. Trussell Contraceptive failure in the United States. , 2004, Contraception.

[77]  J. Cheng,et al.  The effect of a levonorgestrel-releasing intrauterine device on human endometrial oestrogen and progesterone receptors after one year of use. , 1999, Human reproduction.

[78]  V. Odlind,et al.  Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. , 1994, Contraception.

[79]  C. la Vecchia,et al.  Oestrogen replacement treatment and the risk of endometrial cancer: an assessment of the role of covariates. , 1993, European journal of cancer.

[80]  Society for the Advancement of Contraception , 1989 .

[81]  R. Punnonen,et al.  Androgen, estrogen and progestin cytosol receptor concentrations in the normal human endometrium. Effects of intrauterine device. , 1984, Gynecologic and obstetric investigation.

[82]  T. Luukkainen,et al.  Ovarian function in amenorrheic and menstruating users of a levonorgestrel-releasing intrauterine device. , 1984, Fertility and sterility.