Elsevier

Gynecologic Oncology

Volume 149, Issue 1, April 2018, Pages 127-132
Gynecologic Oncology

Levonorgestrel-releasing intrauterine system use is associated with a decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer. Results from the NOWAC Study

https://doi.org/10.1016/j.ygyno.2018.02.006Get rights and content

Highlights

  • We present a population-based prospective cohort study of LNG-IUS users.

  • A mean of 4 years use was associated with 47% reduced ovarian cancer risk.

  • Endometrial cancer risk was reduced by 78%.

  • We found no association between LNG-IUS use and breast cancer.

Abstract

Objective

Women with ovarian cancer have poor survival rates, which have proven difficult to improve; therefore primary prevention is important. The levonorgestrel-releasing intrauterine system (LNG-IUS) prevents endometrial cancer, and recent studies suggested that it may also prevent ovarian cancer, but with a concurrent increased risk of breast cancer. We compared adjusted risks of ovarian, endometrial, and breast cancer in ever users and never users of LNG-IUS.

Methods

Our study cohort consisted of 104,318 women from the Norwegian Women and Cancer Study, 9144 of whom were ever users and 95,174 of whom were never users of LNG-IUS. Exposure information was taken from self-administered questionnaires, and cancer cases were identified through linkage to the Cancer Registry of Norway. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated with Poisson regression using robust error estimates.

Results

Median age at inclusion was 52 years and mean follow-up time was 12.5 (standard deviation 3.7) years, for a total of 1,305,435 person-years. Among ever users of LNG-IUS there were 18 cases of epithelial ovarian cancer, 15 cases of endometrial cancer, and 297 cases of breast cancer. When ever users were compared to never users of LNG-IUS, the multivariable RR of ovarian, endometrial, and breast cancer was 0.53 (95% CI: 0.32, 0.88), 0.22 (0.13, 0.40), and 1.03 (0.91, 1.17), respectively.

Conclusion

In this population-based prospective cohort study, ever users of LNG-IUS had a strongly reduced risk of ovarian and endometrial cancer compared to never users, with no increased risk of breast cancer.

Introduction

In 2012, ovarian cancer caused an estimated 152,000 deaths worldwide [2]. The cumulative risk of ovarian cancer until age 75 is 1.3% in Norway and is similar in the United States [3,4]. The symptoms of ovarian cancer are vague, and there is no screening test. This has led to problems of late diagnosis and a 5-year survival of <50% [5]. Thus, ovarian cancer ranks eighth in cancer incidence, but fifth in cancer mortality among women [4]. Primary prevention therefore remains the best available measure against ovarian cancer [5].

Risk of ovarian cancer is reduced by 15–29% for every 5 years of oral contraceptive (OC) use, and globally, OC use prevents an estimated 30,000 cases of ovarian cancer each year [6]. Long-term OC use also reduces the risk of endometrial cancer, with 5–9 years of use reducing the risk by 34% [7]. However, OC use increases the risk of breast cancer by up to 38% with >10 years use, and for a minimum of 5 years after cessation [8,9], in addition to carrying other health risks. Prescribing OCs for ovarian cancer prevention to women who do not need contraception is not recommended [10].

The levonorgestrel-releasing intrauterine system (LNG-IUS) was introduced in Norway in 1994. In the Nordic countries, LNG-IUS is the second-most used form of contraception after OCs, and it is the most commonly used form of long-acting reversible contraception [11]. Recently, three Finnish studies have shown that, compared to the general population, LNG-IUS users have a standardized incidence ratio (SIR) of 0.59 for ovarian cancer and 0.46 for endometrial cancer [12,13], but also an increased risk of ductal and lobular breast cancer (SIR 1.20 and 1.33 respectively, increasing to SIR 1.37 and 1.73 with >5 years of use) [14]. However, these studies did not adjust for other hormonal risk factors.

Our study aim was to combine self-reported information on OC use and reproductive factors from the Norwegian Women and Cancer (NOWAC) Study, with registry-based follow-up of cancer cases to compare adjusted risks of ovarian, endometrial, and breast cancer in ever users and never users of LNG-IUS. We also included estimates of the reduction in the risk of endometrial cancer in this nationally representative cohort, given the well-known preventive effect of LNG-IUS use on this cancer [15].

Section snippets

Study cohort

The NOWAC Study is a population-based prospective cohort study designed to investigate the association between hormone use and hormone-dependent female cancers [16]. During 1991–2007, women born between 1927 and 1965 were randomly selected from the Norwegian Population Registry and were sent a questionnaire along with a letter that explained the study. Those who returned a completed questionnaire were enrolled. Statistics Norway replaced participants' names and personal identification numbers

Results

Median age at inclusion was 52 years. Mean follow-up time was 12.5 (standard deviation [SD] 3.7) years for a total of 1,305,435 PY. Among all ovarian and uterine corpus cancers, 4% and 5%, respectively, were non-carcinoma cancers and were excluded. Of the women in the study cohort, 9144 (9%) reported LNG-IUS use during or prior to the data collection period (1998–2007). Among ever users of the LNG-IUS, 85% reported the duration of use. Median age at start of LNG-IUS use was 44 years, and median

Discussion

In this population-based prospective cohort study, women who reported ever use of LNG-IUS showed a strongly reduced risk of both ovarian and endometrial cancer compared to those who did not. LNG-IUS use was not associated with an increased risk of breast cancer.

Conclusion

This study shows that a relatively short period of LNG-IUS use is associated with an almost halved risk of ovarian cancer, while the risk of breast cancer remains unchanged. Our results are in agreement with existing data, and show a negative association in a cohort in which the majority of women were older than in previous studies. Although these findings suggest that, in addition to OCs, LNG-IUS should be considered for inclusion in the prevention strategy against ovarian cancer for

Author contributions

EL and HMB conceived the study. MJ contributed to designing the analyses, interpreted results and drafted the paper. EL and JCT oversaw the analyses, interpreted results and critically revised the paper. TB designed the analyses, carried out analyses, and interpreted the results. HMB carried out preliminary analyses, and MAA carried out final analyses. EL is the PI of the NOWAC Study. All authors read and approved the final manuscript.

Acknowledgements

While employed at UiT, Nicolle Mode contributed to the design of, and scripts for, statistical analysis, as well as contributing text to this paper. The authors are supported by the Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway. JCT has a full-time position at the Medical Faculty, Paris Descartes University, and is the beneficiary of a part-time position at UiT. The funding bodies had no role in the design, collection, analysis, or interpretation of data; in

Conflict of interest statement

We declare that we have no conflicting interests.

References (39)

  • L. Dossus et al.

    Reproductive risk factors and endometrial cancer: the European prospective investigation into cancer and nutrition

    Int. J. Cancer

    (2010)
  • Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies

    Lancet

    (1996)
  • L.S. Mørch et al.

    Contemporary hormonal contraception and the risk of breast cancer

    N. Engl. J. Med.

    (2017)
  • L.J.G.J. Havrilesky et al.

    Oral contraceptive use for the primary prevention of ovarian cancer

  • I. Lindh et al.

    Contraceptive use in the Nordic countries

    Acta Obstet. Gynecol. Scand.

    (2017)
  • T. Soini et al.

    Impact of levonorgestrel-releasing intrauterine system use on the cancer risk of the ovary and fallopian tube

    Acta Oncol.

    (2016)
  • T. Soini et al.

    Cancer risk in women using the levonorgestrel-releasing intrauterine system in Finland

    Obstet. Gynecol.

    (2014)
  • T. Soini et al.

    Levonorgestrel-releasing intrauterine system and the risk of breast cancer: a nationwide cohort study

    Acta Oncol.

    (2016)
  • A. Orbo et al.

    Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial

    BJOG

    (2014)
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    Disclaimer: Some of the data in this article are from the Cancer Registry of Norway. The Cancer Registry of Norway is not responsible for the analysis or interpretation of the data presented.

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