In Vitro Human Endometrial Cells and In Vivo Rat Model Studies Suggest That Ulipristal Acetate Impacts Endometrial Compatibility for Embryo Implantation.

BACKGROUND: Ulipristal acetate (UPA) and levonorgestrel are used as emergency hormonal contraceptives. Although both are highly effective in preventing pregnancy, UPA shows efficacy even when taken up to 120 h after unprotected sexual intercourse. AIMS: To investigate whether the mechanism of UPA's contraceptive action involves post-fertilization effects. METHODS: In vitro and in vivo studies using cultured human endometrial cells and a pre-clinical rat model. RESULTS: Endometrial cells treated with UPA showed changes in the expression of receptivity gene markers and a significant decrease in trophoblast spheroids attached to the cultured cells. In addition, administration of UPA to female unmated rats decreased the expression of implantation-related genes in the endometrium and inhibited the number of implantation sites in the mated group compared to the non-treated group. CONCLUSIONS: These results support that UPA as an emergency contraceptive might have post-fertilization effects that may affect embryo implantation.

Pharmacodynamics and pharmacokinetics of a copper intrauterine contraceptive system releasing ulipristal acetate: A randomized proof-of-concept study.

OBJECTIVES: To assess pharmacodynamic and pharmacokinetic outcomes of a novel copper (Cu) intrauterine system (IUS) releasing ulipristal acetate (UPA) in healthy women. STUDY DESIGN: In this single-blinded, randomized proof-of-concept study, ovulatory women received one of three Cu-IUSs releasing low-dose UPA (5, 20 or 40 µg/d) for 12 weeks. The study included a baseline cycle, three 4-week treatment-cycles and 2 recovery cycles. Primary outcomes included effects of the IUS on bleeding profile, ovarian function, and the occurrence of progesterone receptor modulator associated endometrial changes (PAEC). Pharmacokinetics and safety profile were secondary outcomes. We compared outcomes in treatment-cycle 3 with baseline, using generalized linear mixed models with orthogonal contrasts. RESULTS: We randomized 29 women (5 µg/d = 10, 20 µg/d = 10, 40 µg/d = 9). All had a successful IUS insertion; 27 completed the 12-week treatment period. Compared to baseline, the mean number of bleeding-only days at treatment-cycle 3 declined by 16.7% in the 5 µg/d group (3.6 vs 3.0, p = 0.66), 40.5% in the 20 µg/d group (4.2 vs 2.5, p = 0.14), and 77% in the 40 µg/d group (3.9 vs 0.9, p = 0.002). Most women reported reduction in the amount of bleeding: 4/8, 8/10, and 7/9 for the 5 µg/d, 20 µg/d, and 40 µg/d groups, respectively. During IUS use, ovulation occurred in most cycles [5 µg/d: 23/24 (96%), 20 µg/d: 26/30 (87%), 40 µg/d: 22/27 (81%)]. The frequency of PAEC at IUS removal was 1/10 (10%), 1/10 (10%) and 4/9 (44%) in the 5 µg/d, 20 µg/d, and 4 0 µg/d groups, respectively. No serious adverse events occurred. CONCLUSIONS: Reduction in bleeding, low incidence of PAEC, and no serious adverse events are reassuring findings of the novel Cu-UPA-IUS. The 20 µg/d seems the lowest dose promoting a favorable bleeding profile and limiting PAEC. IMPLICATIONS: The preliminary results of this short-term study of a novel copper intrauterine system (IUS) delivering ulipristal acetate showed reduction of bleeding, low incidence of progesterone receptor modulator associated endometrial changes, and absence of serious adverse events. By preventing copper-induced increase in bleeding, this IUS could provide a noncontraceptive benefit, especially for women with low hemoglobin.

A randomized controlled pilot study of ulipristal acetate for abnormal bleeding among women using the 52-mg levonorgestrel intrauterine system.

OBJECTIVE: To assess the efficacy of ulipristal acetate (UPA) for reducing abnormal bleeding among women using the 52-mg levonorgestrel intrauterine system (LNG-IUS). METHODS: A randomized, double-blind, placebo-controlled pilot study conducted from September 1, 2016 to September 30, 2018, at the University of Campinas, Brazil. LNG-IUS users reporting prolonged or frequent uterine bleeding for at least 1 year were randomized to receive 5 mg UPA per day for 5 days or placebo at an identical regimen. Bleeding was recorded for 90 days after treatment began and was compared between the groups. RESULTS: Of 94 eligible women, 64 with abnormal bleeding associated with LNG-IUS use declined treatment or device removal after counselling regarding anticipated bleeding patterns. For the 25 study participants, differences were nonsignificant between the UPA and placebo groups for number of days before bleeding stopped and days free of bleeding; however, UPA users displayed a trend for shorter duration before bleeding stopped and longer time free of bleeding. A similar trend for mean number of bleeding days at 30-, 60-, and 90-day follow-up was observed. CONCLUSION: A nonsignificant trend in reduction of abnormal bleeding was observed among LNG-IUS users taking 5 mg UPA per day for 5 days compared with placebo; however, further research is needed. CLINICALTRIALS.GOV: NCT03186586.

A single post-ovulatory dose of ulipristal acetate impairs post-fertilization events in mice.

Ulipristal acetate (UPA) is a selective progesterone receptor modulator used for emergency contraception that has proven to be highly effective in preventing pregnancy when taken up to 120 h after unprotected sexual intercourse. Even though it may act mainly by delaying or inhibiting ovulation, additional effects of UPA on post-fertilization events cannot be excluded. Therefore, the aim of this study was to determine whether a single post-ovulatory dose of UPA could prevent pregnancy using the mouse as a pre-clinical model. Mated females received a single dose of UPA (40 mg/kg) on Day E1.5 or E2.5 (E0.5: copulatory plug detection) and post-fertilization events were evaluated. Our studies revealed that UPA administration produced a significant decrease in the number of conceptuses compared to control. Moreover, UPA-treated females exhibited a lower number of early implantation sites on Day E5.5, despite normal in vivo embryo development and transport to the uterus at E3.5. Administration of UPA produced histological and functional alterations in the uterine horns, i.e., a dyssynchronous growth between endometrial glands and stroma, with non-physiological combination of both fractions compared to controls, and a completely impaired ability to respond to an artificial decidualization stimulus. Altogether, our results show that the administration of a single post-ovulatory dose of UPA impairs mouse pregnancy probably due to an effect on embryo-uterine interaction, supporting additional effects of the drug on post-fertilization events. Although these studies cannot be performed with human samples, our results with the mouse model provide new insights into the mechanism of action of UPA as an emergency contraception method.

A single preovulatory administration of ulipristal acetate affects the decidualization process of the human endometrium during the receptive period of the menstrual cycle.

In order to get further information on the effects of ulipristal acetate (UPA) upon the process of decidualization of endometrium, a functional analysis of the differentially expressed genes in endometrium (DEG) from UPA treated-versus control-cycles of normal ovulatory women was performed. A list of 1183 endometrial DEG, from a previously published study by our group, was submitted to gene ontology, gene enrichment and ingenuity pathway analyses (IPA). This functional analysis showed that decidualization was a biological process overrepresented. Gene set enrichment analysis identified LIF, PRL, IL15 and STAT3 among the most down-regulated genes within the JAK STAT canonical pathway. IPA showed that decidualization of uterus was a bio-function predicted as inhibited by UPA. The results demonstrated that this selective progesterone receptor modulator, when administered during the periovulatory phase of the menstrual cycle, may affect the molecular mechanisms leading to endometrial decidualization in response to progesterone during the period of maximum embryo receptivity.

Study of the effect of ulipristal acetate on human sperm ability to interact with tubal tissue and cumulus-oocyte-complexes.

OBJECTIVE: Ulispristal acetate (UPA) is a selective progesterone receptor modulator widely used for emergency contraception (EC). The described main mechanism of action is by inhibiting or delaying ovulation; however, the postovulatory effects of the drug are still on debate. Therefore, the aim of this study was to determine whether UPA could interfere with human sperm fertilizing ability. STUDY DESIGN: Human motile spermatozoa were incubated under capacitating conditions with or without UPA, and then used to inseminate human tubal explants, mouse cumulus-oocyte complexes and zona-free hamster eggs. The ability of UPA to interact with human sperm progesterone (P)-binding sites was investigated by incubating the cells with fluorescent-labeled P and analyzing them by fluorescence microscopy. RESULTS: UPA did not affect the ability of human sperm to bind to human tubal tissue explants surface or to penetrate the mouse cumulus mass and the zona-free hamster eggs. In addition, concentrations of UPA much higher than those present in the plasma of EC pill users were required to bind to human sperm P-binding sites. CONCLUSIONS: Our study supports a lack of an agonist or antagonist action of UPA on different functional parameters associated with the fertilizing ability of human sperm. IMPLICATIONS: This study provides new functional evidence supporting that the contraceptive action of UPA is not related to effects on human sperm cells, contributing to a better understanding of the mechanism of action of UPA as EC.

In vitro and in vivo effects of ulipristal acetate on fertilization and early embryo development in mice.

STUDY QUESTION: Does ulipristal acetate (UPA), a selective progesterone receptor modulator used for emergency contraception (EC), interfere with fertilization or early embryo development in vitro and in vivo? SUMMARY ANSWER: At doses similar to those used for EC, UPA does not affect mouse gamete transport, fertilization or embryo development. WHAT IS KNOWN ALREADY: UPA acts as an emergency contraceptive mainly by inhibiting or delaying ovulation. However, there is little information regarding its effects on post-ovulatory events preceding implantation. STUDY DESIGN, SIZE, DURATION: This was an in vitro and in vivo experimental study involving the use of mouse gametes and embryos from at least three animals in each set of experiments. PARTICIPANTS/MATERIALS, SETTING, METHODS: For in vitro fertilization experiments, mouse epididymal spermatozoa capacitated in the presence of different concentrations of UPA (0-1000 ng/ml) were used to inseminate cumulus-intact or cumulus-free eggs in the presence or absence of UPA during gamete co-incubation, and the percentage of fertilized eggs was determined. For in vivo fertilization experiments, superovulated females caged with proven fertile males were injected with UPA (40 mg/kg) or vehicle just before or just after mating and the percentage of fertilized eggs recovered from the ampulla was determined. To investigate the effect of UPA on embryo development, zygotes were recovered from mated females, cultured in the presence of UPA (1000 ng/ml) for 4 days and the progression of embryo development was monitored daily. MAIN RESULTS AND THE ROLE OF CHANCE: In vitro studies revealed that the presence of UPA during capacitation and/or gamete co-incubation does not affect fertilization. Whereas the in vivo administration of UPA at the same time as hCG injection produced a decrease in the number of eggs ovulated compared with controls (vehicle injected animals, P < 0.05), no effects on fertilization were observed when UPA was administered shortly before or after mating. No differences were observed in either the percentage of cleaved embryos or the cleavage speed when UPA was present during in vitro embryo culture. LIMITATIONS, REASONS FOR CAUTION: Considering the ethical and technical limitations inherent to the use of human gametes for fertilization studies, the mouse model was used as an approach for exploring the potential effects of UPA on in vivo sperm transport and fertilization. Nevertheless, the extrapolation of these results to humans requires further investigation. WIDER IMPLICATIONS OF THE FINDINGS: This study presents new evidence on the lack of effect of UPA on gamete interaction and embryo development, providing new insights into the mechanism of action of UPA as an emergency contraceptive method with potential clinical implications. These new findings could contribute to increase the acceptability and proper use of UPA as an emergency contraceptive method. STUDY FUNDING/COMPETING INTERESTS: This study was partially supported by a National Agency of Scientific and Technological Promotion (ANPCyT), Argentina grants PICT 2011-061 to D.J.C. and PICT 2011-2023 to P.S.C. None of the authors has any competing interests to declare.

Ulipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens.

BACKGROUND: The days just prior to ovulation are the most crucial for emergency contraception (EC) efficacy. Ulipristal acetate (UPA) and levonorgestrel's (LNG) capacity to inhibit follicular rupture have never been compared directly at this time of the cycle. STUDY DESIGN: Raw data from three pharmacodynamics studies with similar methodology were pooled to allow direct comparison of UPA, LNG and LNG + meloxicam's ability to prevent ovulation when administered orally in the advanced follicular phase, with a leading follicle of ≥ 18 mm. RESULTS: Forty eight LNG-treated (1.5 mg) cycles, 31 LNG (1.5 mg) + meloxicam (15 mg), 34 UPA (30 mg) cycles and 50 placebo cycles were compared. Follicle rupture was delayed for at least 5 days in 14.6%, 38.7%, 58.8% and 4% of the LNG-, LNG + meloxicam-, UPA- and placebo-treated cycles, respectively. UPA was more effective than LNG and placebo in inhibiting follicular rupture (p = .0001), while LNG, when administered at this time of the cycle, was not different than placebo. The addition of meloxicam improved the efficacy of LNG in preventing follicular rupture (p = .0292 vs. LNG; p = .0001 vs. placebo; non-significant vs. UPA). UPA was effective in preventing rupture in the 5 days following treatment, even when administered at the time of the luteinizing hormone (LH) surge (UPA 79%, LNG 14% and placebo 10%). None of the treatments were effective when administered on the day of the LH peak. The median time from treatment to rupture was 6 days during the ulipristal cycles and 2 days in the placebo and LNG/LNG + meloxicam cycles (p = .0015). CONCLUSION: Although no EC treatment is 100% effective in inhibiting follicular rupture when administered in the late follicular phase, UPA is the most effective treatment, delaying ovulation for at least 5 days in 59% of the cycles. LNG is not different from placebo in inhibiting follicular rupture at this advanced phase of the cycle. No treatment was effective in postponing rupture when administered on the day of LH peak.