Fertility-preserving treatments for endometrial intraepithelial neoplasia: the known unknowns

In this issue of the Journal, Yukio Suzuki and colleagues performed a systematic review and meta-analysis evaluating the resolution of endometrial intraepithelial neoplasia within 1 year among women younger than 50 years of age. They found a high rate of resolution with a levonorgestrel-containing intrauterine device (IUD) (96%) compared with 86% with oral progestins (1). Usually, endometrial intraepithelial neoplasia is found in 1% of premenopausal woman with abnormal uterine bleeding (2). It is a precancerous condition (3), and a concurrent endometrial carcinoma is already present in up to 50% of hysterectomy specimens of women with endometrial intraepithelial neoplasia on biopsy (4). Progesterone has been used with success to treat hyperplasia as early as 1961 (5), and its use in treating endometrial intraepithelial neoplasia and even endometrial cancer has been shown to be safe and effective (6). This finding has led some clinicians to consider the levonorgestrel-containing IUD, developed in the 1970s, to offer it for the treatment of atypical hyperplasia, endometrial intraepithelial neoplasia (7) and endometrial cancer (8). Because of the high risk of endometrial intraepithelial neoplasia being associated with or evolving into endometrial cancer, the definitive treatment for women with endometrial intraepithelial neoplasia remains surgery. Despite this practice, some women who are not surgical candidates and young women who wish to delay definitive surgery to preserve fertility will attempt progesterone treatment. Considering the increasing trend in delaying childbearing in modern society (9) and the risk of endometrial intraepithelial neoplasia associated with the growing obesity pandemic (10), it is predictable that more women will elect to pursue progestin treatment for endometrial intraepithelial neoplasia to maintain fertility. The present systematic review and meta-analysis includes 21 studies (1). Most studies were single-arm exposure, with only 1 randomized controlled trial. In total, 824 premenopausal women with endometrial intraepithelial neoplasia were included, of whom 459 (55.7%) were treated with oral progestin and 365 (44.3%) were treated with levonorgestrel-containing IUD. Despite important heterogeneity between the studies in both study groups, the pooled best complete response proportion within 12 months did not differ statistically between oral treatment vs levonorgestrel-containing IUDs. Importantly, this meta-analysis adds to our knowledge regarding the specific population of premenopausal women with endometrial intraepithelial neoplasia because most of the available literature is heterogenous with regard to women’s age and histology. Despite the best efforts of the authors to apply statistical analyses and control for all the factors available to them, incorporating single-arm, retrospective case series with only 1 level I evidence trial (11) has its limitations. The 1 study with level I evidence concerned a Norwegian multicenter (17 centers) randomized study that was also the only study included in the Cochrane review on the same subject in 2018 (8). Briefly, this study included 153 women and compared 3 arms of treatment: levonorgestrel-containing IUDs (20 μg levonorgestrel per 24 hours; Mirena, Bayer, Whippany, NJ); oral medroxyprogesterone acetate (10 mg administered for 10 days per cycle), or continuous oral medroxyprogesterone acetate 10 mg daily. In this study, however, only 40 women were 44 years of age or younger, and only 19 women had a biopsy-proven complex atypical hyperplasia. This low sample size hampered the level of evidence pertaining to the study question of the meta-analysis in this issue. Response to progestins is not universal, and factors associated with failure remain to be elucidated (12). Body mass index (13,14) and diabetes (15,16) have been proposed as being associated with lower response rates to progestins, and recent data have shown that 23% of patients with endometrial intraepithelial neoplasia treated by progestins experienced obesity and 14.6% had polycystic ovary syndrome (17). A relatively large study from California compared 176 women treated with systemic progestins for endometrial intraepithelial neoplasia vs 69 treated with levonorgestrel-containing IUDs (18) and found that women with elevated body mass index achieved higher complete response with levonorgestrel-containing IUDs than with oral therapy. In nonatypical hyperplasia, regression rates with levonorgestrel-containing IUDs and oral therapy were similar in obese patients, but in this study, levonorgestrel-containing IUD treatment appeared to have a higher regression rate than did oral therapy in patients with a healthy body mass index (19). Considering all the studies, it appears that levonorgestrel-containing IUDs are either equal to or better than oral therapy to reverse endometrial intraepithelial neoplasia, but they are not necessarily associated with improved fertility outcomes, as the present study shows. Despite the excellent resolution rate at 12 months, high relapse rates of endometrial intraepithelial neoplasia have been described with progestin therapy (20), indicating that progestins are most often not curative for endometrial intraepithelial neoplasia, probably related to the underlying causes, which include variations in key genes such as PTEN, PIK3CA, and FGFR2 (21). Progestin treatment for endometrial intraepithelial neoplasia, either by levonorgestrel-containing IUDs or by oral progestins, should be considered a bridging option for women who want to preserve fertility and achieve childbearing and not regarded as a definite treatment. The present review and meta-analysis represents the highest-quality data available at present to counsel women regarding response rates to oral progestins and levonorgestrel-containing IUDs, providing reassurance concerning high response rates at 12 months with both treatment approaches. The choice of optimal progestin treatment will ultimately depend on tolerability, side effects, relapse rates, fertility rates, and long-term outcomes. No new data were generated or analyzed for this editorial. Gabriel Levin, MD (Writing—original draft), Walter Gotlieb, MD PhD (Conceptualization; Supervision; Writing—review & editing). G.L. is sponsored by the Israel Cancer Research Fund of Montreal for his fellowship in gynecologic oncology. G.L has no disclosures. W.G has no disclosures. The funder had no role in the design of the study; the collection, analysis, or interpretation of the data; or the writing of the manuscript and decision to submit it for publication.

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