Levonorgestrel‐releasing intrauterine system and breast cancer risk: A systematic review and meta‐analysis

Abstract

IntroductionEpidemiological studies have shown that some hormonal contraceptive methods are associated with increased breast cancer risk, especially if used over long periods. Our objective was to conduct a systematic review and meta‐analysis of the literature on the risk of breast cancer development in women using the 52‐mg levonorgestrel‐releasing intrauterine system (LNG‐IUS).Material and methodsWe performed a thorough review of peer‐reviewed publications from 10 January 1999, through 31 July 2019, using combinations of search terms for breast cancer risk and LNG‐IUS in the Medline, EMBASE, LILACS (Latin American and Caribbean Health Sciences Literature), and Scielo databases. This review was registered in PROSPERO (CRD42017059076). Studies reporting breast cancer risk estimates among healthy users of LNG‐IUS were included according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐analysis) criteria. Two authors performed data extraction, and a third author resolved disagreements. The quality of evidence was evaluated using the Downs and Black instrument. A funnel plot was generated, and a linear regression test of funnel plot asymmetry was used to assess publication bias. Finally, we performed a random‐effects model (owing to high study heterogeneity) meta‐analysis of seven suitable studies, stratified by the age distribution of patients (<50 years, ≥50 years, and mixed).ResultsWe identified 96 studies and manually cross‐referenced and excluded duplicate articles. Seventy articles were excluded on the basis of the inclusion and exclusion criteria, resulting in the assessment of 26 full‐text articles. Eight articles were considered adequate for inclusion in this systematic review, and seven studies were included in the meta‐analysis. Three publications were case‐control studies and five were cohort studies. According to the Downs and Black instrument, 5 studies were rated as “good” and 3 studies were deemed “fair”. Our meta‐analysis results indicated increased breast cancer risk in LNG‐IUS users: for all women, odds ratio (OR) = 1.16 (95% CI 1.06‐1.28, I2 = 78%, P < .01); for women aged <50 years, OR = 1.12 (95% CI 1.02‐1.22, I2 = 66%, P = .02); and for women aged ≥50 years, OR = 1.52 (95% CI 1.34‐1.72, I2 = 0%, P = .84).ConclusionsCurrent evidence suggests that LNG‐IUS users have an increased breast cancer risk regardless of age and indication. The effect of LNG‐IUS on breast cancer risk seems to be larger in older users. However, our systematic review detected methodological issues across the available studies, and confounding factors may be responsible for at least a fraction of the risk effects associated with LNG‐IUS use. Nevertheless, users of LNG‐IUS should be aware of these trends. We believe that caution is needed, and risks should be balanced against proven health benefits (eg effective treatment of heavy menstrual bleeding and avoidance of surgical interventions), when prescribing LNG‐IUS for long periods of use, especially in women with other known breast cancer risk factors such as old age, obesity, and familial predisposition.

The risks and benefits of hormone replacement therapy before and after a breast cancer diagnosis

“…9,14,15 A recent meta-analysis of observational data suggests an increased risk in all users of the levonorgestrel intra-uterine system, which is greater in women over 50. 16 Risk may not be elevated if dydrogesterone or micronised progesterone is used in preference to synthetic progestogens, but further confirmatory evidence is needed; 13,14,17 Risk of diagnosis is not elevated in past users of HRT; 9 Risk is limited to lean women (i.e. not overweight or obese); 5 There does not appear to be a dosage effect; 15 There is no additive effect in women at elevated personal risk due to a family history or high-risk benign breast condition; 5,15 In women with premature ovarian insufficiency (POI), it is recommended that years of HRT exposure should be counted from the age of 50 and not at the age of HRT commencement when POI is diagnosed.…”

“…9,14,15 A recent meta-analysis of observational data suggests an increased risk in all users of the levonorgestrel intra-uterine system, which is greater in women over 50. 16 Risk may not be elevated if dydrogesterone or micronised progesterone is used in preference to synthetic progestogens, but further confirmatory evidence is needed; 13,14,17…”

PROgesterone Therapy for Endometrial Cancer Prevention in Obese Women (PROTEC) Trial: A Feasibility Study

“…This is particularly important if the LNG-IUS is being used for endometrial protection rather than an established clinical indication, and should be a focus of future work. There is no evidence that the LNG-IUS increases the risk of cardiometabolic disorders in obese women [48], but a recent systematic review found LNG-IUS users have a modestly increased breast cancer risk (odds ratio =1.16 (95% CI 1.06-1.28, I2 =78%, p<0.01), although most of the included studies failed to adjust for BMI [49]. Clearly this is an important area for further research.…”

Depressive Disorder With Panic Attacks After Replacement of an Intrauterine Device Containing Levonorgestrel: A Case Report

“…Due to the localized release of the drug, blood serum levels of levonorgestrel are lower compared to other hormonal contraceptives, and ADRs were supposed to occur less pronounced or mainly in the initial months of use. However, an increased risk of breast cancer ( 2 ) and an emerging evidence regarding mood disorders and suicide attempts ( 3 – 6 ) arises the question of clinically relevant systemic and in particular psychotropic effects of LNG-IUS. Previous studies investigated ADRs only over a time period of 3 to 5 years after implantation ( 7 – 9 ).…”