The aim of the present article was to evaluate endometrial safety of the ulipristal acetate (UPA) treatment for uterine symptomatic fibroids by reviewing the relevant studies and to provide confidence in SPRM (Selective Progesterone Receptor Modulators) clinical use. We designed a review protocol according to PRISMA guidelines and electronic databases search. The databases searched were PubMed, Embase and Cochrane for terms "ulipristal acetate", "endometrium" and "fibroid" or synonyms. After screening, 41 full-text studies were retained, with 9 included selected: 7 randomized controlled, one prospective observational case control and one off label including 1997 patients treated with UPA. Dosage, interval and endometrial aspects at biopsy were described. UPA-induced non-physiological histological changes of the endometrium were reported by 5 studies. The overall quality of the studies was good. No premalignant or malignant endometrial changes were reported. Evidences provided by the study are consistent-UPA can be prescribed for conservative or pre-surgical treatment of fibroids without concern on possible endometrial malignancies.
Ulipristal acetate is increasingly used for several clinical indications, like emergency contraception and pre-treatment of uterine fibroids. It has mixed progesterone agonist and antagonist effects in the myometrium and endometrium. Due to its progesterone antagonistic effect, an unopposed estrogen effect could occur which could cause (pre-)malignant lesions in the endometrium. Several studies have been performed to evaluate this possible increased risk for endometrial malignancies when using ulipristal acetate. The specific spectrum of morphological changes due to ulipristal acetate, named progesterone receptor modulator associated endometrial changes (PAEC), occurs to be reversible after discontinuing ulipristal acetate. In this systematic review we provide a detailed overview of the literature on histopathological endometrial changes and imaging characteristics of the endometrium in ulipristal acetate users. We performed an extensive search in Embase.com, Wiley/Cochrane Library and PubMed in accordance with the prisma guidelines. All studies published as full papers in peer reviewed journals using ulipristal acetate reporting on endometrial changes were included, independent of clinical indication, dosage taken and duration of therapy. No language restrictions were applied. Ten studies with a total of 1450 participants were included. Seven were randomized clinical trials and three prospective cohort studies. A quality assessment of all included studies was performed. In only five of ten studies an endometrial biopsy was performed during treatment. All of these studies described specific histological non-physiological endometrial changes (PAEC) due to ulipristal acetate, varying from 41 to 78.8% of all patients. Three of these studies also performed follow-up biopsies after discontinuing ulipristal acetate. The percentage of PAEC decreased from 62% to 0%, 78.8% to 0% and from 59% to 6-7% after the treatment period. In six of 1450 women (0.4%) endometrial hyperplasia was reported during or after ulipristal acetate use. Five were simple hyperplasia, one biopsy showed simple atypical endometrial hyperplasia that resolved into benign secretory endometrium by the end of the treatment. One case of endometrial adenocarcinoma was reported, however this does not seem to be related to ulipristal acetate use, since it was already present at the baseline biopsy. In eight of ten studies a transvaginal ultrasound or MRI was performed at any moment to assess the endometrial thickness before, during and after treatment. Most studies showed a transient increase of endometrial thickness during treatment, which returned to normal within a few weeks after discontinuing ulipristal acetate. Based on the literature found in this systematic review, follow-up after a maximum of four courses of ulipristal acetate did not report any non-reversible (pre-)malignant lesions of the endometrium. Most studies focused on short term use of ulipristal acetate and their follow-up period was limited. Therefore, we believe more information concerning long term (intermittent) use is needed before it can be concluded that its use is completely safe.
OBJECTIVES: We assessed the evidence about management of uterine fibroids. Specifically, we sought to determine effectiveness of interventions, risks of harm, and whether individual or fibroid characteristics influence outcomes.
DATA SOURCES: We searched MEDLINE® via PubMed® and Embase® to identify publications, as well as reviewed the reference lists of included studies.
METHODS: We included studies published in English from January 1985 to September 2016. We identified randomized clinical trials to assess outcomes and harms of interventions. We used data from trials in a meta-analysis to estimate probability and timing of subsequent interventions for fibroids based on initial type of intervention. To describe risk of unrecognized leiomyosarcoma, we included studies that allowed calculation of prevalence of leiomyosarcoma discovered at the time of surgery for masses believed to be fibroids. We also identified publications that indicated operative approaches to removal of leiomyosarcoma tissue and built models to estimate survival. We extracted data, assessed risk of bias, and rated the strength of evidence for informing care.
RESULTS: Of 97 included randomized trials, 43 studies assessed medications, 28 assessed procedures, and 37 assessed surgeries. Gonadotropin-releasing hormone (GnRH) agonists, mifepristone, and ulipristal reduced fibroid size and improved fibroid-related symptoms, including bleeding and quality of life (moderate strength of evidence [SOE] except quality of life for GnRH agonist [low SOE]). Several other medications have promise but are not supported by sufficient evidence. Uterine artery embolization (UAE) (high SOE) as well as high intensity focused ultrasound (low SOE) are effective for decreasing fibroid size/volume. Few other outcomes are well investigated for high intensity focused ultrasound. UAE studies reported improved outcomes for bleeding (moderate SOE), and quality of life (moderate SOE). Myomectomy and hysterectomy improved q uality of life (both low SOE). Few well-conducted trials directly compared different treatment options. No studies were designed to evaluate expectant management, and evidence is insufficient to guide clinical care. Subsequent intervention ranged from 0 to 44 percent in studies that followed women after initial fibroid treatment. At 2-year followup, subsequent intervention rates were lowest for initial medical management and higher for UAE and myomectomy, especially among younger women. No individual characteristics of women or their fibroids were definitely associated with likelihood of intervention benefits or patient satisfaction. These findings were limited by the number and size of available studies. Using data from 160 studies, we estimated that among 10,000 women having surgery for presumed fibroids, between 0 and 13 will have a leiomyosarcoma detected. Of the surgical approaches, the 5-year survival after leiomyosarcoma diagnosis was 30 percent with power morcellation (95% Bayesian credible interval [BCI]: 13% to 61%), 59 percent with scalpel morcellation (BCI: 33% to 84%), and 60 percent with intact removal (BCI: 24% to 98%).
CONCLUSION: A range of interventions are effective for reducing fibroid size and improving symptoms. Some medications and procedures also improve quality of life. Few studies directly compare interventions. The risk of encountering a leiomyosarcoma at the time of fibroid surgery is low, and the method of fibroid removal may influence survival. Evidence to guide choice of intervention is likely best when applied in the context of individual patient needs and preferences.
The aim of the present article was to evaluate endometrial safety of the ulipristal acetate (UPA) treatment for uterine symptomatic fibroids by reviewing the relevant studies and to provide confidence in SPRM (Selective Progesterone Receptor Modulators) clinical use. We designed a review protocol according to PRISMA guidelines and electronic databases search. The databases searched were PubMed, Embase and Cochrane for terms "ulipristal acetate", "endometrium" and "fibroid" or synonyms. After screening, 41 full-text studies were retained, with 9 included selected: 7 randomized controlled, one prospective observational case control and one off label including 1997 patients treated with UPA. Dosage, interval and endometrial aspects at biopsy were described. UPA-induced non-physiological histological changes of the endometrium were reported by 5 studies. The overall quality of the studies was good. No premalignant or malignant endometrial changes were reported. Evidences provided by the study are consistent-UPA can be prescribed for conservative or pre-surgical treatment of fibroids without concern on possible endometrial malignancies.
