Hormone-Releasing IUD Cancer Risk Mixed

Norra MacReady

July 10, 2014

A levonorgestrel-releasing intrauterine device (IUD) may protect users against cancers of the endometrium, ovary, pancreas, and lung, but increase their risk for breast cancer, a new study suggests.

The breast cancer finding "is of concern, and studies with more detailed demographic and epidemiologic data are needed," Tuuli Soini, MD, from the Department of Obstetrics and Gynecology, Hyvinkää Hospital, Finland, and colleagues write in an article published in the August issue of Obstetrics & Gynecology.

Using data from administrative registers in Finland, Dr. Soini and coauthors analyzed data on all Finnish women between 30 and 49 years of age who were reimbursed for the levonorgestrel-releasing IUD between 1994 and 2007 for the treatment of menorrhagia. The researchers obtained information on cancer cases from the Finnish Cancer Registry. Hospitals and clinics throughout Finland have reported virtually every cancer case in the nation to the registry since 1953. The authors also used cross-sectional national surveys on health behaviors to control for cancer confounders such as smoking, physical activity, diet, and socioeconomic status.

They classified the women according to age in 5-year increments and then estimated the expected number of cancers by multiplying the number of woman-years in each group by the cancer incidence among all Finnish women during the same period. They then divided the number of observed cases by the number of expected cases to arrive at a standardized incidence ratio. The women were followed-up from the time of their first or second purchase of the hormone-releasing IUD until December 31, 2009, or when they reached 55 years of age, died, emigrated, or underwent gynecologic surgery, whichever came first.

During the study period, there were 2781 cases of cancer among 93,843 women who used the levonorgestrel-releasing IUD. Among the 14,234 women who purchased at least 2 IUDs, 454 incident cancer cases were diagnosed after the second IUD purchase. The cancer incidence among users of the hormone-releasing IUD was 7% higher than expected compared with women who did not use the IUD, with an excess of 188 cases. Among women who bought at least 2 IUDs, there was an excess of 76 cases, for an increase of 20%.

Compared with the general population, the standardized incidence ratio for endometrial adenocarcinoma after at least 1 levonorgestrel-releasing IUD purchase was 0.46 (95% confidence interval [CI], 0.33 - 0.64; 37 observed compared with 80 expected cases; P < .001), and it was 0.25 (95% CI, 0.05 - 0.73; 3 observed compared with 12 expected cases; P < .01) after 2 purchases. For all forms of ovarian cancer, after 1 purchase, the standardized incidence ratio was 0.60 (95% CI, 0.45 - 0.76; 59 observed compared with 99 expected cases; P < .001).

There were also fewer observed than expected cases of ovarian cancer after 2 purchases, but the difference was not statistically significant (standardized incidence ratio, 0.51; 95% CI, 0.20 - 1.04; 7 observed compared with 13.7 expected cases). Similarly, the authors observed a significantly lower incidence of lung and pancreatic cancer among women using the levonorgestrel-releasing IUD than in the general population (P < .01 for both).

The standardized incidence ratio for breast cancer after at least 1 purchase was 1.19 (95% CI, 1.13 - 1.25; 1542 observed compared with 1292 expected cases; P < .001). Among users with 2 or more IUD purchases, the standardized incidence ratio was 1.40 (95% CI, 1.24 - 1.57; 271 observed compared with 193.2 expected cases; P < .001). The standardized incidence ratios increased over time, especially after 5 years.

Progestins inhibit endometrial cell proliferation and ovulation and sometimes cause amenorrhea, which could help explain the lower rates of endometrial and ovarian cancer seen, the authors write. The decrease in lung and pancreatic cancer may be in part a hormonal effect and in part a result of the healthier lifestyle pursued by the IUD users, who were less likely to smoke than the general population.

The effect of levonorgestrel on breast tissue may be more complex, the authors write. "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," they warn. "Women using a hormonal intrauterine system for menorrhagia may represent a selected group with different characteristics than the reference population."

Study drawbacks include the inability to adjust for all potential confounders, such as parity and family history of cancer, and the possible use of estrogens by women in the control group. The authors conclude that the levonorgestrel-releasing IUD may lower a woman's risk for lung, pancreatic, and endometrial cancer but is associated with a worrisome increase in breast cancer incidence.

This research was supported by research grants from Helsinki University Hospital and Hyvinkää Hospital. The authors have disclosed no relevant financial relationships.

Obstet Gynecol. 2014;124:292-299.

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