Systematic review and meta‐analysis on the impact of the levonorgestrel‐releasing intrauterine system in reducing risk of ovarian cancer

Abstract Background Ovarian carcinoma (OC) is one of the most widespread tumors in the world and is characterized by low survival rates. Objective To determine whether the levonorgestrel‐releasing intrauterine system (LNG‐IUS) can prevent OC. Search strategy The literature until December 2020 were systematically reviewed according to the PRISMA Statement for Reporting Systematic Reviews (PROSPERO: CRD42019137957). Selection criteria Studies assessing the impact of LNG‐IUS on the risk of OC were included. Data collection and analysis Data were extracted independently by two authors to ensure accuracy and consistency. Main results A total of 34 323 records were obtained, of which three satisfied the inclusion criteria. In total, 1687 events of OC in a population of 20 461 311 person‐years were considered. Data pooling revealed that the use of LNG‐IUS did not confer a lower risk of OC relative to the never‐use of LNG‐IUS, with an estimated odds ratio of 0.66 (95% confidence interval 0.41–1.08; I2 = 84%; P = 0.002). Conclusion The meta‐analysis did not demonstrate a preventive role of LNG‐IUS on OC. However, it was carried out on a few papers, and a definitive conclusion on the topic still cannot be drawn. Further studies are indicated in the future to define the impact of LNG‐IUS on OC. The meta‐analysis carried out on three papers did not demonstrate a preventive role of the levonorgestrel‐releasing intrauterine device on ovarian cancer.


| INTRODUC TI ON
Ovarian carcinoma is one of the most widespread and lethal tumors in women: it represents the seventh most common cancer in the world and the eighth cause of death from cancer in women, with 3.6% of cases and 4.3% of deaths. 1 The lifetime risk of developing ovarian tumors is estimated to be 1.4%. Ovarian carcinoma is usually asymptomatic at the early stages and tends to become symptomatic when ovarian carcinoma has already metastasized. 2 After 5 years, the rates of survival change with stage at the time of diagnosis: 94% for localized disease; 73% for regional disease; and 28% for distant disease. The epithelial category represents 60% of all ovarian tumors, of which 90% are malignant. 2 Sex cord-stromal and germ cell tumors usually have benign features and are less frequent. The first serotype accounts for 8% of all ovarian tumors, afflicting postmenopausal women in particular, while the germ cell type accounts for 25% of all ovarian tumors, and it presents mostly at around 20 years of age. 3 Given its heterogeneous entity, several theories have been postulated on the development of the disease. Serous tubal intraepithelial carcinoma in the fimbrias of the fallopian tubes is believed to be the major precursor of high-grade serous cancer, while the surface epithelium of the ovary may give origin to low-grade cancer. 4 Endometrial cells or endometriosis play a role in the development of endometrioid and clear cell carcinoma, 5 while gastrointestinal cells may be the precursors of mucinous ovarian carcinoma. 6 Familiarity, reproductive history, and hormone fluctuations have been demonstrated to play a major role in the development of ovarian carcinoma. Nulliparity, postmenopausal hormone therapy (HT), and family history of ovarian carcinoma are directly related to the tumor risk. 7,8 Conversely, tubal ligation, pregnancies, and combined oral contraceptives (COC) have been inversely associated with the development of ovarian carcinoma. COCs are believed to prevent the disease by inhibiting ovulation, reducing menstrual bleeding, and retrograde menstruation. 9 However, less evidence is available for progestin-only hormonal contraceptives, in particular for levonorgestrel-releasing intrauterine systems (LNG-IUS).
LNG-IUS was introduced in Norway in 1994, and its use is nowadays widespread. 10 It was initially developed as a method of contraception and subsequently used also as therapy for heavy menstruation, dysmenorrhea, and endometrial protection. 11 The device releases levonorgestrel (LNG) into the uterine cavity, where endometrial vessels soak up the hormone. The progestin level reaches a peak after the first few hours of insertion and a plateau after the first weeks 12 ; thereafter, the systemic concentration decreases. The concentration of LNG becomes similar in the myometrium and the fallopian tubes, while locally, into the uterine cavity, the concentration is higher. 13 While the impact of LNG-IUS on endometrial epithelium is well defined and associated with a reduction in the risk of endometrial cancer, the effect on ovarian function is less clear.
The first cycles may be anovulatory due to a higher concentration of hormone plasma. After the first year, the level of LNG decreases, and it becomes insufficient to suppress hypothalamic-pituitary-ovarian function without affecting systemic estradiol concentration. 14,15 Interestingly, recent studies suggest a protective role of LNG-IUS not only on endometrial cancer but also on the development of ovarian carcinoma; however, its role is still unclear. 11,16,17 As a consequence, the aim of the present review was to investigate the impact and effectiveness of the LNG-IUS on risk of ovarian carcinoma by systematically reviewing the current literature and performing a meta-analysis.

| MATERIAL S AND ME THODS
The present systematic review was conducted and reported according to both the PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses 18 and the Meta-Analysis of Observational Studies in Epidemiology guidelines 19 (PROSPERO registration code: CRD42019137957). Study objectives, eligibility criteria, outcome definitions, search strategy, process of data extraction, statistical analyses, and method of study quality assessment were all defined in a protocol. Investigators are experienced in systematic reviews. [20][21][22][23][24] Studies assessing the impact of LNG-IUS on the risk of ovarian carcinoma were included. Letters to the editor, conference abstracts, book chapters, guidelines, Cochrane reviews, and expert opinions were excluded. The occurrence of OC in the population exposed or not exposed to LNG-IUS was considered an outcome measure.
To identify potentially eligible studies, PubMed, Scopus, Cochrane Library, and ISI Web of Science were searched (up to December 1, 2020) using EndNote x8 (Clarivate Analytics). A combination of keywords and text words were used: "levonorgestrel-releasing"; "intrauterine system"; "intrauterine device"; "intrauterine implant"; "intrauterine contraceptives"; "ovarian cancer"; "ovarian carcinoma"; and "ovarian neoplasm." An example of the complete search strategy used for the PubMed search is presented in Appendix S1. Two reviewers independently screened the titles and abstracts of the records that were retrieved through the database searches. No limitations to language were applied. A manual search was also performed using the reference lists of key articles to include additional relevant articles. Both reviewers independently recommended studies for the full-text review. Full texts of records recommended by at least one reviewer were screened independently by the same two reviewers and assessed for inclusion in the systematic review. Disagreements between reviewers were solved by consensus.
Data were extracted using a piloted form specifically designed for capturing information on study and characteristics. Information about study design, settings, sample sizes and features of participants, exposure and outcome assessment, duration of follow-up, confounding factors, and main findings were extracted from each study.
The impact of the exposition was measured after the LNG-IUS exposition, and the occurrence of ovarian carcinoma in the population was analyzed. Data were extracted independently by two authors to ensure accuracy and consistency. The authors were emailed about studies that were felt potentially might have unpublished data about the considered outcome. Two reviewers independently screened the full texts of records included in the systematic review and assessed the quality of the studies using the Newcastle-Ottawa Scale (NOS).
The NOS contains four items under the selection domain, one item under the comparability domain, and three items under the outcome domain. A star scoring system, from zero to nine stars, is used for the assessment of study quality, such that the highest-quality studies are awarded one star per item, except for the comparability domain, for which two stars for a single item can be assigned. Disagreements between reviewers were solved by consensus.
The number of events of ovarian cancer in the population-years according to the use (current or previous) versus non-use of LNG IUS was collected from the considered studies. The pooling of results was done according to the random-effects method of DerSimonian and Laird. 25 The odds ratio (OR) was considered as the measure of effect. I 2 and tau 2 indexes were used to quantify heterogeneity between studies, and the null hypothesis that all studies share a common effect size was tested. All the analyses were performed using Revman 5.4 software.

| RE SULTS
The electronic database search provided a total of 34 323 results ( Figure 1). After excluding any duplicates, there were 5 008 citations left. Of them, 4 990 were not relevant to the review based on title and abstract screening. Three further records found with a manual search were added. A total of 21 studies were considered for full-text assessment, of which 19 were excluded for the following reasons: there were five reviews; three studies did not address clinical questions; 10 studies did not evaluate the LNG-IUD; and one study had a population overlapping with an included study published by the same authors. None were excluded for languages other than English. Some answers were received from authors of potential includible papers, and an additional dataset was obtained. 26 Finally, three studies met the inclusion criteria and were incorporated into the final assessment. 10,26,27 The main characteristics of these studies are listed in Table 1. All considered studies showed satisfactory quality according to the NOS.
Soini et al. 27    However, the considered studies carry some critical risk of bias.

Newcastle-Ottawa Scale
Soini et al. 27 did not adjust the risk of ovarian carcinoma for the use of oral contraceptives, and rates of ovarian carcinoma are compared to those expected in the general population. 27  of women, when restricted to women whose hormonal history was known and followed up to the first switch in hormonal contraception, accounting for the potential lingering effect of prior use of COCs. 26 As a consequence, the data pooling revealed no effect of LNG-IUS on risk of ovarian cancer. A limitation of the present meta-analysis is the lack of stratification for histotypes since only one study investigated this parameter. 27 Since endometrioid tumors originate from endometriotic cells 5 and express high levels of progesterone receptors (PRs), it may be expected that LNG may involve a specific and more pronounced protective effect on this histotype. 37 Another limitation can be found in the limited number of considered studies, revealing the urgent need for further studies on this topic.
The meta-analysis could not demonstrate that LNG-IUS has a preventive role in the development of ovarian cancer. However, since only a few papers were retrieved, a definitive conclusion on the topic cannot be drawn, and further studies are needed to better define the impact of LNG-IUS on ovarian carcinoma.
Moreover, the effect of the duration of exposure to LNG-IUS and any beneficial role on cancer susceptibility while the device is inserted represent further interesting aspects to investigate in the future.

ACK N OWLED G M ENTS
Open Access Funding provided by Universita degli Studi di Genova.
[Correction added on 07-May-2022, after first online publication: CRUI-CARE funding statement has been added].

CO N FLI C T S O F I NTE R E S T
The authors have no conflicts of interest.

AUTH O R CO NTR I B UTI O N S
GD was responsible for data collection and MF for data analysis and interpretation of results. GD and MF developed the project and wrote the manuscript. FB, SC, and CG contributed to critical revision, and SF was responsible for the conception of the study.