Globally, breast cancer is the most common malignancy with approximately 1.68 million new cases diagnosed annually. Endometrial cancer is the most frequent gynecologic cancer in developed countries with approximately 319,000 new cases annually worldwide. Half these cancers arise in the Western world.1 Both physiologic and malignant transformations of breast and endometrial cells are regulated by sex hormones.2,3
The levonorgestrel-releasing intrauterine system was primarily developed for contraception, but the indications have later extended to treatment of menorrhagia and protection from endometrial hyperplasia during estrogen therapy. This hormonal intrauterine system releases continuously high intrauterine concentrations of levonorgestrel, causing endometrial decidualization and atrophic changes.4 These endometrial effects have made this system a promising alternative for treatment of endometrial hyperplasia,5 which is a potential precursor of endometrial cancer. The risk for endometrial cancer is reported to be decreased during postmenopausal use of hormonal intrauterine system in combination with estradiol,6 but the risk for breast cancer is reported to be increased.7
There are only two studies published on the breast cancer risk of premenopausal levonorgestrel-releasing intrauterine system users, and neither reports an increased risk.8,9 The relationship between levonorgestrel-releasing intrauterine system use and the incidence of other cancers remains unknown.
Our primary aim in this nationwide cohort study was to test the hypothesis that the incidence of endometrial adenocarcinoma is decreased among premenopausal levonorgestrel-releasing intrauterine system users. Our second aim was to assess the risks of other common cancers among premenopausal levonorgestrel-releasing intrauterine system users.
MATERIALS AND METHODS
In this observational nationwide cohort study, we collected a database of all Finnish women who in 1994–2007 were between the ages of 30 and 49 years (n=93,843) and had received reimbursement for the levonorgestrel-releasing intrauterine system for treatment of heavy menstrual bleeding. The study data were obtained from administrative registers in Finland. The data linkages were done using the unique personal identity code issued by The Finnish Population Register Centre since 1967 to all citizens and permanent residents of Finland and used as the identification key in all national registers. The data on levonorgestrel-releasing intrauterine system reimbursements were extracted from the national Reimbursement Register of the Social Insurance Institution, which contains data on purchases of the levonorgestrel-releasing intrauterine system since 1994. The register uses the anatomical therapeutic chemical classification system.
The data on cancer cases were extracted from the Finnish Cancer Registry, which receives notifications of all cancer cases from hospitals and pathology laboratories, covering virtually 100% of diagnosed cancers in Finland since 1953.10 Since 1961, reporting of new cancer cases is mandatory by law in Finland. Cancer notifications submitted to the Finnish Cancer Registry are stored in a database, and regular quality crosschecks are done between the cancer register data and other administrative registers (Central Population Register, Statistics Finland) to ensure the correctness of data. The data of cancer risk-related confounders (ie, smoking, alcohol consumption, physical activity, diet, socioeconomic status) were derived from a series of cross-sectional national health behavior surveys. A nationwide random sample from the Finnish population aged 15–64 years has been drawn annually during 1978–2002 with some 5,000 Finnish people receiving a mailed questionnaire each year. The annual samples for the survey were drawn from the Finnish Population Register. Among women, the response rate has varied between 75% and 86%.11 Women aged 30–49 years who had returned the questionnaire in the health behavior survey were analyzed (4,056 levonorgestrel-releasing intrauterine system users and 25,801 nonusers). Information on socioeconomic status was obtained from the census files of Statistics Finland. Information on health behaviors was self-reported. We calculated women-years at risk, in 5-year age groups, starting from the first purchase of the levonorgestrel-releasing intrauterine system and ending on December 31, 2009, or on emigration, the 55th birthday, bilateral or unilateral salpingectomy, salpingo-oophorectomy or oophorectomy, hysterectomy, or death, whichever occurred first. We obtained information on surgical procedures since 1986 from the Hospital Discharge Register of the National Institute of Health and Welfare. This register has summary information on patients discharged from public and private hospitals since 1969 with coverage of almost 100%.12 The data accuracy and completeness of the Finnish Hospital Discharge Register data have been reported to be good.13 To analyze the effect of duration of levonorgestrel-releasing intrauterine system use on cancer risks, we also analyzed study participants with at least two levonorgestrel-releasing intrauterine system purchases. In these analyses, the follow-up started from the second purchase of a levonorgestrel-releasing intrauterine system.
We calculated the expected numbers of cancers by multiplying the number of woman-years in each 5-year age group by the corresponding cancer incidence among all Finnish women during the same period. Standardized incidence ratio was calculated by dividing the number of observed cancer cases by the number of expected cancer cases. Ninety-five percent confidence intervals (CIs) for the standardized incidence ratios were based on the assumption that the number of observed cases represents a Poisson distribution.14 A standardized incidence ratio with P<.01 was considered statistically significant.
All statistical analyses in the health behavior survey data were performed using StataMP 11.15 Logistic regression analyses (odds ratios [ORs] with 95% CIs) were conducted to assess the association between individual health behavior factors and use of the levonorgestrel-releasing intrauterine system. This study was approved by the institutional review boards of Hyvinkää Hospital and Helsinki University Hospital. The Finnish National Centre for Welfare and Health, after consulting the data protection authority, approved the use of the confidential national register data in this research.
During the study period 1994–2009, a total of 93,843 levonorgestrel-releasing intrauterine system users were followed for 855,324 women-years at risk, and 2,781 cancer cases were diagnosed among levonorgestrel-releasing intrauterine system users during the follow-up (Table 1). Altogether, 14,234 women had purchased at least two levonorgestrel-releasing intrauterine systems, and 454 incident cancer cases were diagnosed after the second purchase (Table 1).
The observed number of cancer cases among all levonorgestrel-releasing intrauterine system users was 7% higher than the expected number (Table 2). In absolute numbers, a total of 188 excess of cancer cases was detected during follow-up. There was a 20% excess among women with two levonorgestrel-releasing intrauterine system purchases (76 cancer cases more than expected).
The standardized incidence ratio for endometrial adenocarcinoma after at least one levonorgestrel-releasing intrauterine system purchase was 0.46 (95% CI 0.33–0.64; 37 observed compared with 80 expected cases) and 0.25 (95% CI 0.05–0.73; three observed compared with 12 expected cases) after two purchases. The standardized incidence ratio for uterine sarcomas was not lower than in the reference population (Table 2).
The standardized incidence ratio for breast cancer among all levonorgestrel-releasing intrauterine system users was 1.19 (95% CI 1.13–1.25; 1,542 observed compared with 1,292 expected cases). Among users with two levonorgestrel-releasing intrauterine system purchases, the standardized incidence ratio was 1.40 (95% CI 1.24–1.57; 271 observed compared with 193 expected cases). Increased standardized incidence ratios for breast cancer were found, especially in age categories of 45–54 years (Table 3). The standardized incidence ratio increased along with follow-up time.
The standardized incidence ratio for ovarian cancer in general was 0.60 (95% CI 0.45–0.76; 59 observed compared with 99 expected cases) (Table 2).
Compared with the background population, the incidences for lung cancer and pancreatic cancer among the levonorgestrel-releasing intrauterine system users were significantly lower (Table 2). We did not observe significant standardized incidence ratios for the other cancers (Table 2).
We also calculated standardized incidence ratios for women exposed to only one levonorgestrel-releasing intrauterine system. In this analysis, the follow-up ended at the date of the second levonorgestrel-releasing intrauterine system purchase. The standardized incidence ratio for endometrial cancer of users with only one levonorgestrel-releasing intrauterine system was 0.50 (95% CI 0.35–0.70; 34 observed compared with 68 expected cases), whereas the standardized incidence ratio after two or more purchases was 0.25 (95% CI 0.05–0.73; three observed compared with 12 expected cases). The respective standardized incidence ratios for breast cancer were 1.16 (95% CI 1.09–1.22; 1,271 observed compared with 1,099 expected cases) and 1.40 (95% CI 1.24–1.57; 271 observed compared with 193 expected cases).
Four percent of the whole levonorgestrel-releasing intrauterine system user cohort had participated in the national health behavior survey among a random sample from the Finnish population aged 15–64 years during 1978–2002. In that sample, the levonorgestrel-releasing intrauterine system users had a higher socioeconomic position and were more often married as compared with the nonusers. The levonorgestrel-releasing intrauterine system users were less often overweight (body mass index [calculated as weight (kg)/[height (m)]2] more than 25; 17.1% compared with 20.5%; OR 0.80, 95% CI 0.73–0.87) and were less often smokers (22.1% compared with 25.6%; OR 0.80, 95% CI 0.74–0.87) compared with nonusers. On the other hand, they consumed alcohol slightly more often and went to work by car instead of walking or biking.
Our main finding is that levonorgestrel-releasing intrauterine system use for treatment of menorrhagia during reproductive years was associated with a lower incidence of endometrial, ovarian, pancreatic, and lung cancers than expected. Levonorgestrel-releasing intrauterine system use was associated with a higher than expected incidence of breast cancer.
The incidence of endometrial adenocarcinoma after first levonorgestrel-releasing intrauterine system purchase was 54% lower than in the general population, and the reduction was pronounced with continued use. This is in line with a study on postmenopausal women.6 Risk for endometrial cancer among nonhormonal intrauterine device users is decreased by half,16 and our results indicate that the risk is even more decreased with the hormonal intrauterine system.
The levonorgestrel-releasing intrauterine system was associated with an increased risk for breast cancer, in contrast to earlier studies. A postmarketing study on 17,360 women using the levonorgestrel-releasing intrauterine system for contraception found no elevation in breast cancer risk.8 However, the follow-up of 10 years in that study was probably too short and the epidemiologic methodology was also unusual, because the breast cancer incidence of levonorgestrel-releasing intrauterine system users over the entire follow-up period was compared with breast cancer incidence of a single year in 1998. In a retrospective, population-based case–control study with women younger than age 50 years at the time of breast cancer diagnosis, the risk of premenopausal breast cancer was not increased in levonorgestrel-releasing intrauterine system users relative to copper intrauterine device users.9
The effects of progestins have been described to be clearly different in the endometrium and in the breast. Progestins inhibit endometrial cell proliferation, but in the breast, the action is more complex.17,18 Although the mechanism of action of a hormonal intrauterine system is primarily local, a small amount of levonorgestrel is absorbed into the systemic circulation,19 and significant individual variations have been reported.20,21 Our finding of an increased standardized incidence ratio for breast cancer after 5 or more years of follow-up may reflect causality between extended progestin exposure and cancer risk, but the results should be interpreted with caution in light of the limitations of the study. Women using a hormonal intrauterine system for menorrhagia may represent a selected group with different characteristics than the reference population.
Our data show a strongly decreased risk for ovarian cancer among levonorgestrel-releasing intrauterine system users. Theories of the general mechanisms behind the reduced ovarian cancer risk are suppression of ovulation22 and obstructing retrograde transportation of endometrial epithelial cells.23 The hormonal intrauterine system does not significantly affect ovarian function24 but frequently causes amenorhea,25 which hypothetically reduces transportation of carcinogenic agents into fallopian tubes.
The incidence of cancer of the pancreas and lung was strongly decreased. Part of this can be explained by a lower frequency of smokers in the levonorgestrel-releasing intrauterine system user cohort but not all. Hypothetically, exposure to levonorgestrel may play a role in this. Both the normal and neoplastic pancreas and lung are reported to express steroid hormone receptors26,27 and exogenous steroid hormones may modify the risk for these cancers.27,28 Progesterone receptor expression is also reported to be a strong protective factor for lung cancer.27
Strengths of this study are a long follow-up with a large number of women. Up to 15% of fertile women used the levonorgestrel-releasing intrauterine system in Finland during the study period. Up to 60% of purchased levonorgestrel-releasing intrauterine systems were used for menorrhagia (L. Kaikkonen, Bayer Schering Pharma, Turku, Finland, personal communication). In addition, the national registers of Finland have a high level of coverage enabling this type of research.29 We had complete follow-up for surgical operations, emigration, and death. Thus, biases resulting from selective reporting and recall were eliminated.
We could not adjust for all potential confounding factors such as parity, family history of cancer, lifestyle factors, or use of other exogenous hormones. Whether a larger fraction of the study group than of the reference population was also on estrogen therapy is unknown. If so, the possible joint exposure to both levonorgestrel and estrogen may explain the increased risk of breast cancer among the study group. This potential confounding was minimized by stopping the follow-up at the age of 55 years. The study group was compared with a reference population including also hormonal intrauterine system users and those with previous hysterectomy or salpingo-oophorectomy, which slightly dilutes the risk estimates shown.
This study supports the idea of a protective endometrial effect of the levonorgestrel-releasing intrauterine system, but the increased risk of breast cancer is of concern, and studies with more detailed demographic and epidemiologic data are needed. It is important to always counsel patients about the potential benefits and risks of the hormonal therapies.
1. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon (France): International Agency for Research on Cancer; 2010. Available at: http://globocan.iarc.fr
. Retrieved February 10, 2014.
2. Schindler AE. Progestogen deficiency and endometrial cancer risk. Maturitas 2009;62:334–7.
3. Knutson TP, Lange CA. Tracking progesterone receptor-mediated actions in breast cancer. Pharmacol Ther 2014;142:114–25.
4. Guttinger A, Critchley HOD. Endometrial effects of intrauterine levonorgestrel. Contraception 2007;75(suppl):S93–8.
5. Gallos ID, Ganesan R, Gupta JK. Prediction of regression and relapse of endometrial hyperplasia with conservative therapy. Obstet Gynecol 2013;121:1165–71.
6. Jaakkola S, Lyytinen HK, Dyba T, Ylikorkala O, Pukkala E. Endometrial cancer associated with various forms of postmenopausal hormone therapy: a case control study. Int J Cancer 2011;128:1644–51.
7. Lyytinen HK, Dyba T, Ylikorkala O, Pukkala EI. A case-control study on hormone therapy as a risk factor for breast cancer in Finland: Intrauterine system carries a risk as well. Int J Cancer 2010;126:483–9.
8. Backman T, Rauramo I, Jaakkola K, Inki P, Vaahtera K, Launonen A, et al.. Use of the levonorgestrel-releasing intrauterine system and breast cancer. Obstet Gynecol 2005;106:813–7.
9. Dinger J, Bardenheuer K, Minh TD. Levonorgestrel-releasing and copper intrauterine devices and the risk of breast cancer. Contraception 2011;83:211–7.
10. Teppo L, Pukkala E, Lehtonen M. Data quality and quality control of a population-based cancer registry. Experience in Finland. Acta Oncol 1994;33:365–9.
11. Tolonen H, Helakorpi S, Talala K, Helasoja V, Martelin T, Prättälä R. 25-year trends and socio-demographic differences in response rates: Finnish adult health behaviour survey. Eur J Epidemiol 2006;21:409–15.
12. Keskimäki I, Aro S. Accuracy of data on diagnoses, procedures and accidents in the Finnish hospital discharge register. Int J Health Sci 1991;2:15–21.
13. Sund R. Quality of the Finnish hospital discharge register: a systematic review. Scand J Public Health 2012;40:505–15.
14. Rothman KJ, Greenland S, Lash TL, editors. Modern epidemiology. 3rd ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2008.
15. StataCorp. Stata statistical software: release 11. College Station (TX): StataCorp LP; 2009.
16. Beining RM, Dennis LK, Smith EM, Dokras A. Meta-analysis of intrauterine device use and risk of endometrial cancer. Ann Epidemiol 2008;18:492–9.
17. Yang S, Thiel KW, Leslie KK. Progesterone: the ultimate endometrial tumor suppressor. Trends Endocrinol Metab 2011;22:145–52.
18. Aupperlee M, Kariagina A, Osuch J, Haslam SZ. Progestins and breast cancer. Breast Dis 2005–2006;24:37–57.
19. Luukkainen T, Lahteenmäki P, Toivonen J. Levonorgestrel-releasing intrauterine device. Ann Med 1990;22:85–90.
20. Heikinheimo O, Lehtovirta P, Suni J, Paavonen J. The levonorgestrel-releasing intrauterine system (LNG-IUS) in HIV-infected women—effects on bleeding patterns, ovarian function and genital shedding of HIV. Hum Reprod 2006;21:2857–61.
21. Lockhat FB, Emembolu JO, Konje JC. The efficacy, side-effects and continuation rates in women with symptomatic endometriosis undergoing treatment with an intra-uterine administered progestogen (levonorgestrel): a 3 year follow-up. Hum Reprod 2005;20:789–93.
22. Fathalla MF. Factors in the causation and incidence of ovarian cancer. Obstet Gynecol Surv 1972;27:751–68.
23. Dubeau L. The cell of origin of ovarian epithelial tumours. Lancet Oncol 2008;9:1191–7.
24. Tasci Y, Caglar GS, Kayikcioglu F, Cengiz H, Yagci B, Gunes M. Treatment of menorrhagia with the levonorgestrel releasing intrauterine system: effects on ovarian function and uterus. Arch Gynecol Obstet 2009;280:39–42.
25. Hurskainen R, Teperi J, Rissanen P, Aalto AM, Grenman S, Kivela A, et al.. Quality of life and cost-effectiveness of levonorgestrel-releasing intrauterine system versus hysterectomy for treatment of menorrhagia: a randomised trial. Lancet 2001;357:273–7.
26. Robles-Diaz G, Duarte-Rojo A. Pancreas: a sex steroid-dependent tissue. Isr Med Assoc J 2001;3:364–8.
27. Siegfried JM, Stabile LP. Estrongenic steroid hormones in lung cancer. Semin Oncol 2014;41:5–16.
28. Lee E, Horn-Ross PL, Rull RP, Neuhausen SL, Anton-Culver H, Ursin G, et al.. Reproductive factors, exogenous hormones, and pancreatic cancer risk in the CTS. Am J Epidemiol 2013;178:1403–13.
29. Pukkala E. Biobanks and registers in epidemiologic research on cancer. Methods Mol Biol 2011;675:127–64.