Selective progesterone receptor modulators (SPRMs) have beneficial effects in reducing the size of uterine fibroids and the amount of bleeding, but their endometrial effects have not been seen with other agents. This report describes the morphology of the endometrium after 3 mo of treatment with the SPRM, ulipristal acetate (UPA). In 2 Phase III randomized double-blind controlled clinical trials, 546 patients with uterine myomas were treated with 5 or 10 mg of UPA daily for 13 wk or placebo or gonadotropin-releasing hormone agonist. Endometrial biopsies were taken at screening, end of treatment (13 wk), and after treatment-free follow-up (38 wk). Biopsies were assessed independently by 3 pathologists according to a preset morphologic scheme. After 13 wk, the UPA-treated endometrium showed altered architectural glandular features including extensive cystic dilatation. The glandular epithelium appeared inactive or contained abortive subnuclear vacuolization, occasional mitoses, and apoptosis. Abnormal stromal vessels were commonly seen. There was a high level of agreement between pathologists on the presence or the absence of nonphysiological changes. One case of hyperplasia without atypia and 4 polyps were seen at 13 wk of UPA treatment. Six months after treatment, the endometrium returned to normal histology in the majority of the patients, with 1 polyp and no cases of hyperplasia in the UPA-treated groups, and 2 hyperplasias (1 with and 1 without atypia) in the placebo or the gonadotropin-releasing hormone-agonist groups. Mild reversible thickening of the endometrium occurs in a minority of cases. It is important that pathologists are aware of the spectrum of changes induced by SPRMs to avoid misdiagnoses of endometrial hyperplasia or polyps.
BACKGROUND: The efficacy and safety of oral ulipristal acetate for the treatment of symptomatic uterine fibroids before surgery are uncertain.
METHODS: We randomly assigned women with symptomatic fibroids, excessive uterine bleeding (a score of >100 on the pictorial blood-loss assessment chart [PBAC, an objective assessment of blood loss, in which monthly scores range from 0 to >500, with higher numbers indicating more bleeding]) and anemia (hemoglobin level of ≤10.2 g per deciliter) to receive treatment for up to 13 weeks with oral ulipristal acetate at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) or to receive placebo (48 women). All patients received iron supplementation. The coprimary efficacy end points were control of uterine bleeding (PBAC score of <75) and reduction of fibroid volume at week 13, after which patients could undergo surgery.
RESULTS: At 13 weeks, uterine bleeding was controlled in 91% of the women receiving 5 mg of ulipristal acetate, 92% of those receiving 10 mg of ulipristal acetate, and 19% of those receiving placebo (P<0.001 for the comparison of each dose of ulipristal acetate with placebo). The rates of amenorrhea were 73%, 82%, and 6%, respectively, with amenorrhea occurring within 10 days in the majority of patients receiving ulipristal acetate. The median changes in total fibroid volume were -21%, -12%, and +3% (P=0.002 for the comparison of 5 mg of ulipristal acetate with placebo, and P=0.006 for the comparison of 10 mg of ulipristal acetate with placebo). Ulipristal acetate induced benign histologic endometrial changes that had resolved by 6 months after the end of therapy. Serious adverse events occurred in one patient during treatment with 10 mg of ulipristal acetate (uterine hemorrhage) and in one patient during receipt of placebo (fibroid protruding through the cervix). Headache and breast tenderness were the most common adverse events associated with ulipristal acetate but did not occur significantly more frequently than with placebo.
CONCLUSIONS: Treatment with ulipristal acetate for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids. (Funded by PregLem; ClinicalTrials.gov number, NCT00755755.).
RESEARCH QUESTION: What is the individualized bleeding experience of women with fibroids and anaemia in a 3 month randomized placebo controlled trial (PEARL I) of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA)?
SUMMARY ANSWER: In contrast to continuing excessive regular menstruation in the placebo group, a majority of women treated with UPA (63.1% of those on 5 mg/day and 71.3% of those on 10 mg/day) experienced the rapid onset of amenorrhoea or minimal blood loss [pictorial blood loss assessment chart (PBAC) < 12]. The remainder experienced various patterns of bleeding and intensity of blood loss that are described for the first time, including an association of irregular bleeding on UPA with sub-mucous fibroids.
WHAT IS KNOWN ALREADY: The majority experience on UPA is amenorrhoea but the bleeding experience of the others has not been characterized.
STUDY DESIGN, SIZE, DURATION: A 13 week randomized controlled trial in women, eligible for surgery for uterine fibroids and anaemia, comparing placebo (n = 48), UPA 5 mg (n = 95) or UPA 10 mg (n = 94). The treatment aim was fibroid shrinkage and the primary definitions and outcomes are published elsewhere; here the secondary outcome measure of vaginal bleeding pattern is described.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Women, 18-50 years old, with fibroids and haemoglobin ≤10.2 g/dl, justifying surgery. At least one fibroid was 3-10 cm diameter and uterus ≤16 weeks pregnancy size. All used the daily PBAC methodology in a screening cycle (Ps) and throughout treatment, and for the 4 weeks preceding Week 26 and Week 38 in those who did not have surgery. An excessive menstruation is PBAC > 100. The bleeding patterns were characterized using the classification of Belsey, developed under auspices of WHO.
MAIN RESULTS AND THE ROLE OF CHANCE: In the placebo group, all women had an excessive screening PBAC [median 376; interquartile range (IQR) 241-574]; 81.3% of them had regular menstrual bleeding and the intensity of bleeding remained similar, so that the median PBAC in the next three periods was 90, 92 and 93% of the screening value. Four of the 48 women had spontaneous improvement in bleeding and one developed amenorrhoea and elevation of gonadotrophins. In the placebo group, 22 women provided Week 26 and 21 women provided Week 38 PBAC data. The median Week 26 PBAC (312: IQR 102-524) and Week 38 PBAC (236; IQR 103-465) indicated ongoing excessive bleeding. In the UPA group, screening PBAC confirmed excessive bleeding (UPA 5 mg, median 358; IQR 232-621; UPA 10 mg, median 330; IQR 235-542). UPA was initiated from the start of a menstruation (P1) and no women had regular periods on treatment. Following P1 through the whole of the remaining 13 weeks of UPA treatment amenorrhoea or minimal loss (PBAC < 12 for whole phase) occurred in 63.1% (UPA 5 mg) or 71.3% (UPA 10 mg). The characterization of the individualized bleeding experience of the remaining women on 5 mg and 10 mg UPA, respectively, were infrequent bleeding in 17.9 and 12.8%; frequent or prolonged bleeding or both in 12.7 and 11.7% and irregular bleeding in 5.3 and 3.2%. In those with prolonged, frequent or irregular bleeding there was a high chance that sub-mucous fibroids were present (UPA 5 mg 100% and UPA 10 mg 78.6%) but no correlation with progesterone receptor modulator-associated endometrial changes.
LIMITATIONS, REASONS FOR CAUTION: The follow-up PBAC data at Week 26 and Week 38 are only valid for women who did not have surgical intervention. These groups may not be representative of the groups at screening.
WIDER IMPLICATIONS OF THE FINDINGS: This first detailed description of these SPRM bleeding patterns provides clinicians with an indication of potential responses in women using the SPRM UPA and provides an extended definition of bleeding in untreated women with excessive bleeding and fibroids.
STUDY FUNDING/COMPETING INTEREST(S): Funded by PregLem/Gedeon Richter. D.H.B. is a member of the Scientific Advisory Board of PregLem, and in this role participated in the study design and supervision. Stock originally held in PregLem was given up when PregLem was incorporated into Gedeon Richter; D.H.B. does not currently hold stock. M.A.L. has received payment from Gideon Richter to attend a meeting to present these data (Barcelona, April 2013) but no financial support in preparing the manuscript. B.C.J.M.F. is a member of the Scientific Advisory Board of PregLem and has received fees and grant support from the following companies: Andromed, Ardana, Auxogyn, Ferring, Genovum, Gedeon Richter, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Roche, Schering, Schering Plough, Serono, Watson Laboratories and Wyeth. P.T. is a paid statistical consultant for PregLem SA. E.B. is a full time employee of PregLem and received payment from stocks sold in October 2010 from the company's full acquisition by Gedeon Richter Group.
TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT00755755 (PEARL I).
Selective progesterone receptor modulators (SPRMs) have beneficial effects in reducing the size of uterine fibroids and the amount of bleeding, but their endometrial effects have not been seen with other agents. This report describes the morphology of the endometrium after 3 mo of treatment with the SPRM, ulipristal acetate (UPA). In 2 Phase III randomized double-blind controlled clinical trials, 546 patients with uterine myomas were treated with 5 or 10 mg of UPA daily for 13 wk or placebo or gonadotropin-releasing hormone agonist. Endometrial biopsies were taken at screening, end of treatment (13 wk), and after treatment-free follow-up (38 wk). Biopsies were assessed independently by 3 pathologists according to a preset morphologic scheme. After 13 wk, the UPA-treated endometrium showed altered architectural glandular features including extensive cystic dilatation. The glandular epithelium appeared inactive or contained abortive subnuclear vacuolization, occasional mitoses, and apoptosis. Abnormal stromal vessels were commonly seen. There was a high level of agreement between pathologists on the presence or the absence of nonphysiological changes. One case of hyperplasia without atypia and 4 polyps were seen at 13 wk of UPA treatment. Six months after treatment, the endometrium returned to normal histology in the majority of the patients, with 1 polyp and no cases of hyperplasia in the UPA-treated groups, and 2 hyperplasias (1 with and 1 without atypia) in the placebo or the gonadotropin-releasing hormone-agonist groups. Mild reversible thickening of the endometrium occurs in a minority of cases. It is important that pathologists are aware of the spectrum of changes induced by SPRMs to avoid misdiagnoses of endometrial hyperplasia or polyps.
