The association between levonorgestrel intrauterine devices (LNG-IUDs) and breast cancer risk as highly effective contraceptive and gynecological treatment has attracted much attention. This article aims to systematically review the latest evidence and provide individualized decision support based on risk-benefit assessment for clinical practice.
Research Summary
Intrauterine devices (IUDs) containing levonorgestrel (LNG), such as Mirena, are increasingly used as a highly effective long-acting reversible contraceptive method and treatment for gynecological diseases. However, the potential long-term effects of the progestin component it contains on breast tissue, particularly the association with breast cancer risk, have been the focus of clinical concern and academic debate. This review aims to integrate the latest large-scale epidemiological research evidence, provide an in-depth analysis of the relationship between LNG-IUD and breast cancer risk, and provide evidence-based recommendations for clinical practice.This article systematically reviews large national cohort studies recently published in authoritative journals such as the Journal of the American Medical Association (JAMA) and the American Journal of Obstetrics and Gynecology (AJOG), as well as clinical guidelines and related meta-analyses published by professional institutions such as the American College of Obstetricians and Gynecologists (ACOG), focusing on the relative risk (RR), hazard ratio (HR), absolute risk increase value, and the impact of breast cancer in special populations (such as breast cancer survivors, BRCA gene mutation carriers).The latest evidence suggests that LNG-IUD use is associated with a small increased risk of breast cancer compared to women who do not use hormonal contraception. National cohort studies in Denmark and Sweden reported a relative risk increase of 13% to 40%, respectively [1,2]. However, this increased risk is still low in absolute values, especially in young women. For example, one study stated that there is only one additional case of breast cancer per 7,690 users [3]. The risk appears to be most pronounced in women in the 30-39 age group and has a synergistic effect with a family history of breast cancer [2]. On the other hand, studies have confirmed that LNG-IUDs have significant protective effects against endometrial and ovarian cancers [2]. For breast cancer survivors, particularly those undergoing tamoxifen treatment, existing meta-analyses have shown that the use of LNG-IUDs does not increase the risk of cancer recurrence or metastasis [4].Clinical decisions should be based on a comprehensive assessment of individual risk-benefit and adequate doctor-patient communication. Although LNG-IUDs are statistically weakly associated with breast cancer risk, their absolute risk increment is minimal, and their significant benefits in effective contraception, treatment of menorrhagia, and prevention of gynecologic malignancies cannot be ignored. LNG-IUD remains a safe and effective option for most women without high-risk factors. It should be avoided in patients with a personal history of breast cancer; For women with family history or high-risk factors such as BRCA mutations, individualized trade-offs and informed decision-making are required.
Introduction
Levonorgestrel intrauterine devices (LNG-IUDs) have been widely used worldwide for efficient contraception and effective treatment of various gynecological diseases such as menorrhagia, dysmenorrhea, and endometriosis by continuously releasing low-dose progestin locally in the uterine cavity [5]. Although its progesterone effect is mainly local, it has been confirmed by studies to have systemic absorption and can affect target organs such as the breast [6]。 Given the complex relationship between exogenous hormones and breast cancer risk, the long-term safety of LNG-IUDs, especially whether they increase the incidence of breast cancer, has been a central concern for clinicians and users. In recent years, several large-scale, high-quality epidemiological studies have provided new evidence on this issue, making it possible to quantify and interpret this risk more precisely. This review aims to integrate these latest research findings to provide a scientific basis for clinicians to consult and make decisions about the use of LNG-IUDs in their daily practice.
Summary of the latest research evidence
Breast cancer risk in the general population
Two recent large-scale national cohort studies in Denmark and Sweden have provided the strongest evidence to date for assessing LNG-IUD and breast cancer risk.
Trade-offs of risk: absolute risk vs. multiple benefits
When interpreting the above data, it is important to emphasize the importance of distinguishing between relative and absolute risks. Although the relative risk increase (13% to 40%) sounds alarming, the added value of absolute risk is very limited because the baseline incidence of breast cancer in women of childbearing age is inherently very low. For example, for a woman in her 30s, the baseline risk was about 0.49%, and after using the LNG-IUD, the risk rose to 0.69%, and the absolute risk increased by only 0.2 percentage points [7]. This means that about 500 women need to continue using LNG-IUDs for an additional case of breast cancer to occur.At the same time, the benefits of LNG-IUDs are manifold. In addition to a contraceptive effectiveness of nearly 100%, Swedish studies have confirmed that it significantly reduces the risk of other gynecologic malignancies: a 33% reduction in the risk of endometrial cancer and a 14% reduction in the risk of ovarian cancer [2]. These protective effects, combined with their efficacy in treating gynecologic conditions, constitute a crucial part of the risk-benefit assessment.
Safety for special populations
Breast cancer survivors
In patients with a pre-existing history of breast cancer, the use of any form of hormone therapy should be treated with extreme caution. However, for patients who are partially affected by tamoxifen (TAM) treatment with problems such as endometrial thickening, LNG-IUDs offer a potential solution. A Chinese meta-analysis of five randomized controlled trials (RCTs) showed that the addition of LNG-IUD did not significantly increase the risk of cancer recurrence or metastasis in postoperative breast cancer patients treated with TAM (complication difference RD: 0.03, 95% CI: -0.03-0.08, P=0.29) [4]。 This suggests that LNG-IUD can be a relatively safe option to address gynecological complications caused by TAM under the premise of fully informing about potential risks and conducting close monitoring.
High-risk population (family history/BRCA mutation)
Swedish studies have clearly pointed to the interaction between LNG-IUDs and family history of breast cancer, suggesting that genetic predisposition may amplify the risk of carcinogenesis of exogenous hormones [2]. Nevertheless, several international guidelines, including ESMO and NCCN, consider the use of LNG-IUDs to be acceptable for women with only a family history or who are carriers of BRCA gene mutations (without cancer), but emphasize the need for individualized counseling and decision-making [8]
Before placing an LNG-IUD for any woman, a comprehensive risk informant must be given, including a small increase in breast cancer risk (especially the concept of absolute risk), a balance between a reduced risk of other gynecologic cancers, and its highly effective contraceptive and therapeutic benefits. A detailed personal and family history of breast cancer should be asked and recorded.
For the majority of women of childbearing age who have no personal history of breast cancer and no family history of breast cancer in the first degree, the benefits of LNG-IUD far outweigh their small risk of breast cancer, and should be regarded as a safe and effective first-line long-acting contraceptive and related disease treatment option.
Family history of breast cancer/BRCA mutation carrier: should not be considered an absolute contraindication. It should be explained that synergies may lead to a higher risk increase than in the general population, but the absolute risk increase may still be clinically acceptable. Shared decision-making is made based on the urgency of the need for contraception, the need for prevention of other gynecological cancers, and personal values.
Have a personal history of breast cancer: generally not recommended. For patients with newly diagnosed breast cancer, removal of the LNG-IUD that is already in place should be recommended. The only exception may be that for patients undergoing TAM treatment with severe endometrial problems, retention or placement of the LNG-IUD may be considered after discussion by a multidisciplinary team (MDT) and the patient's full informed and consent, and more intensive gynecological and breast follow-up.