Progesterone Receptor Modulator Ulipristal Acetate Research Articles

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding: the UCON randomised controlled trial and mechanism of action study

Background Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. The levonorgestrel-releasing intrauterine system is an effective long-term treatment but is discontinued by many due to unpredictable bleeding, or adverse effects. The selective progesterone receptor modulator ulipristal acetate is used to treat symptomatic fibroids but long-term efficacy for the symptom of heavy menstrual bleeding, irrespective of presence of fibroids, is unknown. Objectives To determine whether ulipristal acetate is more effective at reducing the burden of heavy menstrual bleeding than levonorgestrel-releasing intrauterine system after 12 months of treatment in women with and without fibroids. We investigated mechanism of action of ulipristal acetate in a subset of 20 women. Design Randomised, open-label, parallel group, multicentre trial with embedded mechanistic study. Setting Ten UK hospitals. Participants Women with heavy menstrual bleeding aged 18 and over with no contraindications to levonorgestrel-releasing intrauterine system or ulipristal acetate. Interventions Three 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or continuous levonorgestrel-releasing intrauterine system following allocation in a 1 : 1 ratio using a web-based minimisation procedure. Main trial outcome measures Primary outcome was quality-of-life measured by menorrhagia multi-attribute scale at 12 months. Secondary outcomes included menstrual bleeding and patient satisfaction. Impact on fibroid size, endometrial appearance and liver function was also collected. Mechanistic study outcome Cellular markers for endometrial cell structure and function, determined from endometrial biopsies; volume of uterus and fibroids and microcirculation parameters were determined from magnetic resonance images. Results Sample size was increased from 220 to 302 as a result of temporary halt to recruitment due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate and the COVID-19 pandemic led to a premature closure of recruitment, with 118 women randomised to each treatment and 103 women completing 12-month menorrhagia multi-attribute scale scores prior to this point. Primary outcome scores substantially improved in both arms, but at 12 months there was no evidence of a difference between those receiving three cycles of ulipristal acetate [median score category: 76–99, interquartile range (51–75 to 100), n = 53] and levonorgestrel-releasing intrauterine system [median score category: 76–99, interquartile range (51–75 to 100), n = 50; adjusted odds ratio 0.55, 95% confidence interval 0.26 to 1.17; p = 0.12]. Rates of amenorrhoea were much higher in those allocated ulipristal acetate compared with the levonorgestrel-releasing intrauterine system (12 months: 64% vs. 25%, adjusted odds ratio 7.12, 95% confidence interval 2.29 to 22.2). There was no evidence of a difference in other participant-reported outcomes. There were no cases of endometrial malignancy and no hepatotoxicity due to ulipristal acetate use. Mechanistic study results Ulipristal acetate produced a reversible reduction in endometrial cell proliferation, as well as reversible alteration of other endometrial cellular markers. Ulipristal acetate did not produce a reduction in the volume of the uterus irrespective of coexisting fibroids, nor an effect on uterine microvascular blood flow. Limitations The urgent safety measures and premature closure of recruitment impacted final sample size. Conclusions We found no evidence of a difference in quality of life between the two treatments, but ulipristal acetate was superior to levonorgestrel-releasing intrauterine system at inducing amenorrhoea. Ulipristal acetate currently has restricted availability due to concerns regarding hepatotoxicity. Future work There is a need to develop new, safe, effective and fertility-sparing medical treatments for heavy menstrual bleeding. The observed acceptability and effectiveness of ulipristal acetate warrants further research into the selective progesterone receptor modulator class of pharmacological agents. Study registration This trial is registered as ISRCTN 20426843.

Effects of Ulipristal Acetate on Reactive Oxygen Species and Proinflammatory Cytokine Release by Epithelial and Stromal Cells from Human Endometrium and Endometriosis.

Endometriosis is a condition characterized by increased oxidative stress and chronic inflammation, which can be treated with progestins and other progesterone receptor ligands. However, some patients are refractory to this treatment and the reason is uncertain. Here we investigated the effects of the selective progesterone receptor modulator ulipristal acetate (UPA) on proliferation, reactive oxygen species (ROS), and proinflammatory cytokine production by endometriotic cells and endometrial cells from women with histologically proven endometriosis (n=22) and endometriosis-free controls (n=6). Epithelial and stromal cells were isolated and treated in triplicate for 24h with 1 μM, 10 μM, or 100 μM UPA. Cells were tested for proliferation and ROS production, while cell supernatants were assayed for interleukin (IL)-6, C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor (TNF)-α concentrations. Proliferation, ROS production, and IL-6 and CCL2 secretion were increased in non-stimulated epithelial and stromal cells from endometriotic lesions compared to endometrial cells from endometriosis patients and controls. UPA induced a dose-dependent increase of cell proliferation only in endometriosis, while enhancing ROS production by all cell types evaluated. UPA reduced CCL2 production in controls but failed to do that in endometriosis, whereas TNF-α was undetectable. We conclude that treatment of endometriotic cells with UPA stimulated in vitro proliferation and ROS production and failed to revert the proinflammatory cytokine excess that characterized these cells, unravelling possible mechanisms of drug resistance in the treatment of endometriosis.

Measurement of changes in uterine and fibroid volume during treatment of heavy menstrual bleeding (HMB).

Does application of an unbiased method for analysis of magnetic resonance (MR) images reveal any effect on uterine or fibroid volume from treatment of heavy menstrual bleeding (HMB) with three 12-week courses of the selective progesterone receptor modulator ulipristal acetate (SPRM-UPA)? Application of an unbiased method for analysis of MR images showed that treatment of HMB with SPRM-UPA was not associated with a significant reduction in the volume of the uterus or in the volume of uterine fibroids. SPRM-UPA shows therapeutic efficacy for treating HMB. However, the mechanism of action (MoA) is not well understood and there have been mixed reports, using potentially biased methodology, regarding whether SPRM-UPA has an effect on the volume of the uterus and fibroids. In a prospective clinical study (with no comparator), 19 women with HMB were treated over a period of 12 months with SPRM-UPA and uterine and fibroid size were assessed with high resolution structural MRI and stereology. A cohort of 19 women aged 38-52years (8 with and 11 without fibroids) were treated with three 12-week courses of 5 mg SPRM-UPA given daily, with four weeks off medication in-between treatment courses. Unbiased estimates of the volume of uterus and total volume of fibroids were obtained at baseline, and after 6 and 12 months of treatment, by using the Cavalieri method of modern design-based stereology in combination with magnetic resonance imaging (MRI). Bland-Altman plots showed good intra-rater repeatability and good inter-rater reproducibility for measurement of the volume of both fibroids and the uterus. For the total patient cohort, two-way ANOVA did not show a significant reduction in the volume of the uterus after two or three treatment courses of SPRM-UPA (P = 0.51), which was also the case when the groups of women with and without fibroids were considered separately (P = 0.63). One-way ANOVA did not show a significant reduction in total fibroid volume in the eight patients with fibroids (P = 0.17). The study has been performed in a relatively small cohort of women and simulations that have subsequently been performed using the acquired data have shown that for three time points and a group size of up to 50, with alpha (Type I Error) and beta (Type II Error) set to 95% significance and 80% power, respectively, at least 35 patients would need to be recruited in order for the null hypothesis (that there is no significant reduction in total fibroid volume) to be potentially rejected. The imaging protocol that we have developed represents a generic paradigm for measuring the volume of the uterus and uterine fibroids that can be readily incorporated in future studies of medical treatments of HMB. In the present study, SPRM-UPA failed to produce a significant reduction in the volume of the uterus or the total volume of fibroids (which were present in approximately half of the patients) after either two or three 12-week courses of treatment. This finding represents a new insight in respect of the management of HMB using treatment strategies that target hormone-dependence. The UPA Versus Conventional Management of HMB (UCON) trial was funded by the EME Programme (Medical Research Council (MRC) and National Institutes of Health Research (NIHR)) (12/206/52). The views expressed in this publication are those of the authors and not necessarily those of the Medical Research Council, National Institute for Health Research, or Department of Health and Social Care.Medical Research Council (MRC) Centre grants to the Centre for Reproductive Health (CRH) (G1002033 and MR/N022556/1) are also gratefully acknowledged. H.C. has clinical research support for laboratory consumables and staff from Bayer AG and provides consultancy advice (All paid to Institution) for Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc., and Myovant Sciences GmbH. H.C. has received royalties from UpToDate for an article on abnormal uterine bleeding. L.W. has received grant funding from Roche Diagnostics (Paid to Institution). All other authors have no conflicts to declare. The study reported here is an embedded mechanism of action study (no comparator) within the UCON clinical trial (registration ISRCTN: 20426843).

Decreased growth differentiation factor 9, bone morphogenetic protein 15, and forkhead box O3a expressions in the ovary via ulipristal acetate.

Folliculogenesis is a complex process involving various ovarian paracrine factors. During folliculogenesis, vitamin D3 and progesterone are significant for the proper development of follicles. This study aimed to investigate the effects of vitamin D3 and selective progesterone receptor modulator ulipristal acetate on ovarian paracrine factors. In the study, 18 female Wistar-albino rats were randomly divided into three groups: control group (saline administration, n=6), vitamin D3 group (300 ng/day vitamin D3 oral administration, n=6), and UPA group (3 mg/kg/day ulipristal acetate oral administration, n=6). Ovarian tissue was analyzed by histochemistry and immunohistochemistry. For quantification of immunohistochemistry, the mean intensities of growth differentiation factor 9, bone morphogenetic protein 15, and forkhead box O3a expressions were measured by Image J and MATLAB. Blood samples were collected for the analysis of serum anti-Müllerian hormone levels by ELISA. Atretic follicles and hemorrhagic cystic structures were observed in the UPA group. After immunohistochemistry via folliculogenesis assessment markers, growth differentiation factor 9, bone morphogenetic protein 15, and cytoplasmic forkhead box O3a expressions decreased in the UPA group (p<0.05). Anti-Müllerian hormone level did not differ significantly between the experimental groups (p>0.05). Ulipristal acetate negatively affects folliculogenesis via ovarian paracrine factors. The recommended dietary vitamin D3 supplementation in healthy cases did not cause a significant change.

Molecular subclass of uterine fibroids predicts tumor shrinkage in response to ulipristal acetate.

Precision medicine carries great potential for management of all tumor types. The aim of this retrospective study was to investigate if the two most common genetically distinct uterine fibroid subclasses, driven by aberrations in MED12 and HMGA2 genes, respectively, influence response to treatment with the progesterone receptor modulator ulipristal acetate. Changes in diameter and mutation status were derived for 101 uterine fibroids surgically removed after ulipristal acetate treatment. A significant difference in treatment response between the two major subclasses was detected. MED12 mutant fibroids had 4.4 times higher odds of shrinking in response to ulipristal acetate treatment as compared to HMGA2 driven fibroids (95% confidence interval 1.37-13.9; P= 0.013), and in a multivariate analysis molecular subclassification was an independent predictive factor. Compatible with this finding, gene expression and DNA methylation analyses revealed subclass specific differences in progesterone receptor signaling. The work provides a proof-of-principle that uterine fibroid treatment response is influenced by molecular subclass and that the genetic subclasses should be taken into account when evaluating current and future uterine fibroid therapies.

Ulipristal acetate and pregnancy outcome-an observational study.

Is the failure of the selective progesterone receptor modulator ulipristal acetate (UPA) as emergency contraception (EC; 30mg, single) or inadvertent exposure for myoma treatment (5mg/d) in pregnancy associated with a higher risk of birth defects, spontaneous abortion (SAB) or elective termination of pregnancy (ETOP)? We did not find an increased risk for birth defects, SABs or ETOPs after UPA exposure during implantation and early embryogenesis. Pregnancy outcome data after exposure to UPA are very limited. In cases of EC failure or unplanned pregnancy during myoma treatment, women need well-grounded risk assessment to minimize anxiety and prevent unjustified termination of pregnancy. Observational study of prospectively ascertained pregnancies from the German Embryotox institute with UPA exposure (EC, n= 95; myoma, n= 7). Four retrospectively reported pregnancy outcomes were evaluated separately. A total of 226 requests on ulipristal were directed to the German Embryotox institute during the study period 2010-2018. Outcomes of pregnancies exposed-(i) precycle, (ii) preconceptional or (iii) first trimester-were ascertained using standardized questionnaires. Descriptive statistics were applied. Failed EC with UPA resulted in 95 prospectively ascertained pregnancies, of which 56 had completed follow-up: 37 live births, 7 SABs and 12 ETOPs. There was no major birth defect. Just 34% of women had taken UPA during the fertile window. Seven prospectively enrolled pregnancies were treated for myoma and had known pregnancy outcomes: five healthy live births and two SABs. Among the four retrospectively reported pregnancies after EC, there was one child diagnosed with Beckwith-Wiedemann syndrome (BWS). Our limited sample size does not allow concluding safety of UPA use in pregnancy. We provide a preliminary basis for reassuring women who wish to carry their pregnancy to term after EC or myoma treatment with UPA. However, because of the report of a BWS after UPA exposure, a possible epigenetic effect could not be excluded and requires further evaluation. This work was performed with financial support from the German Federal Institute for Drugs and Medical Devices (BfArM). All authors declare that they have no conflicts of interest. Registered with the German Clinical Trial Register (DRKS00015155).

Predictive Factors of Response to Selective Progesterone Receptor Modulator (Ulipristal Acetate) in the Pharmacological Treatment of Uterine Fibroids.

Background: Selective progesterone receptor modulator ulipristal acetate (UPA) is a drug used in management of symptomatic myomas. It was observed that the response to UPA treatment in uterine myomas varied amongst patients. An attempt was thus made at establishing predictive factors conducive to better reaction to treatment with UPA. The aim of this study was to assess the efficacy of UPA treatment in women with myomas, depending on pretreatment myomas’ volume, number of myomas, age of patients, estrogenic status of women, and pretreatment blood flow in uterine arteries. Materials and methods: The study included patients with one to four myomas. The UPA treatment was a preparation stage for surgical treatment in all patients. The study group was divided into the subgroups according to pretreatment myomas’ volume, number of myomas, age of patients, estrogenic status of women, and pretreatment blood flow in uterine arteries. Results: A better effect of reduction in size of myomas after UPA treatment was noted when pretreatment myomas’ volume was lower than 30 cm3. A significant reduction in fibroids’ size was observed after UPA therapy independently of the number of myomas and age of patients. A good response after the UPA therapy was observed when pretreatment estradiol concentration was below 50 pg/mL and when uterine artery resistance index (RI) was above 0.8. Conclusions: Our research demonstrates that treatment with ulipristal acetate is an efficient method in preoperative preparation of patients with uterine fibroids. The most important factor of positive response to UPA therapy is myoma volume. The number of myomas and patient’s age do not interfere with effects of UPA therapy. Pretreatment estradiol concentration is significant, yet secondary for the effects of therapy. The UPA therapy has no impact on blood flow in the uterine arteries and no adverse influence on estradiol concentrations.

Clinical results of long-term use of selective progesterone receptor modulators and gonadotropin releasing hormone agonists in the treatment of uterine leiomyoma

The study was performed to assess the effectiveness of drug treatment of uterine leiomyoma in premenopausal women using progesterone receptor modulator ulipristal acetate (UPA ) in comparison with gonadotropin-releasing hormone agonists (aGnRH). The I group consisted of 30 women with uterine leiomyoma who received aGnRH in extended course plus hormone replacement medication. Group II included 15 women receiving periodic treatments with UPA . The control group included 30 healthy women of late reproductive age. Median follow-up for women was 18 months. The results showed that the UPA provides a longer lasting effect after the end of therapy, unlike aGnRH, leading to the elimination of the uterine leiomyoma symptoms in 86.7% of women

First synthesis and characterization for the stereoisomers of Ulipristal acetate

The three stereoisomers, 11α,17α-isomer I, 11α,17β-isomer II and 11β,17β-isomer III are related substances of the selective progesterone receptor modulator Ulipristal acetate. Herein, we presented an efficient and practical synthesis approach to deliver these three stereoisomers for the first time, and also confirmed the structure of the key intermediate 5a by single-crystal X-ray analysis. Our research will be of immense help for organic chemists to study the impurity profile of Ulipristal acetate.

A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free, method of contraception

ObjectiveTo determine whether a 3-month contraceptive vaginal ring (CVR) delivering ulipristal acetate (UPA) can inhibit ovulation in 90% of cycles. Study DesignThis was a randomized dose-finding parallel group clinical trial. Fifty-five healthy women with normal ovulation at baseline were randomized to receive a low-dose (1500 μg/day) or a high-dose (2500 μg/day) UPA-CVR for two consecutive 12-week treatment periods, followed by a recovery cycle. A subgroup of women received levonorgestrel (LNG) 1.5 mg orally twice (at the end of both 12-week ring periods) or once (at the end of the 24-week treatment). The primary outcome was ovulation suppression assessed by transvaginal ultrasound and hormone levels. Secondary outcomes included endometrial safety and bleeding patterns. ResultsAll subjects showed normal ovulation at baseline and recovery. Ovulation suppression was seen in 81.8% (95% CI: 73.3%, 88.5%) and 86.1% (95% CI: 78.1%, 92%) of treatment cycles with low and high-dose, respectively. Benign progesterone receptor modulator associated endometrial changes (PAEC) were seen during treatment; 78.8% at week 24, but resolved at recovery cycle. A few cases of heavy bleeding occurred near the end of the 24-week treatment, but a single dose of LNG every 12 weeks reduced the increase in endometrial thickness during the second treatment period and prevented excessive bleeding. ConclusionThe 3-month UPA-CVR may become an effective long-acting, user-controlled estrogen-free contraceptive. The greatest suppression of ovulation was seen with the 2500-μg/day ring. ImplicationsThe 3-month CVR delivering UPA 2500 μg/day can become an effective user-controlled estrogen-free contraceptive method. Benign PAEC during treatment returns to normal after discontinuation. The prevention of occasional excessive withdrawal bleeding, either by a progestin or by using higher UPA levels to increase follicle suppression may permit prolonged treatment.

Erratum to: Update of Conservative Systemic Treatment of Uterine Fibroids

Abstract Uterine fibroids are a common disease in women and lead to different symptoms, like pain and bleeding disorders. Apart from surgical treatment, there are many medical treatment options, which are presented in this article. Combined oral contraceptives and Levonorgestrel-releasing intrauterine systems are possible options for bleeding disorders that are a consequence of uterine fibroids. Gonadotropin-releasing hormone agonists and the new selective progesterone receptor modulator ulipristal acetate can effectively reduce myoma mass and vaginal bleeding rate. Ulipristal acetate should especially be considered for treatment in symptomatic women, as it has only a few noteworthy side effects.

Update of Conservative Systemic Treatment of Uterine Fibroids

Uterine fibroids are a common disease in women and lead to different symptoms, like pain and bleeding disorders. Aside from surgical treatment, there are many medical treatment options, which are presented in this article. Combined oral contraceptives and Levonorgestrel-releasing intrauterine systems are possible options for bleeding disorders that are a consequence of uterine fibroids. Gonadotropin-releasing hormone agonists and the new selective progesterone receptor modulator Ulipristal acetate can effectively reduce myoma mass and vaginal bleeding rate. Ulipristal acetate should especially be considered in symptomatic women, as it has only a few noteworthy side effects.

Carcinogenicity and Chronic Rodent Toxicity of the Selective Progesterone Receptor Modulator Ulipristal Acetate

Carcinogenic properties of ulipristal acetate (UPA), a selective progesterone receptor modulator developed for the treatment of benign gynecological conditions such as uterine fibroids, were assessed in a 26-week carcinogenicity study in transgenic TgRasH2 mice and a 104-week study in Sprague Dawley rats. Dose levels used in the mouse study were 15, 45, or 130 mg/kg/day and for the ratstudy the doses used were 1, 3, or 10 mg/kg/day. Vehicle and water controls were part of both studies and a positive control, N-Nitroso-N-methylurea intraperitoneally, was included in the transgenic mouse assay. Survival at all dose levels was similar to vehicle controls in both sexes of both species and there was no evidence of any UPA-induced carcinogenicity in either species. Rats receiving UPA had decreased incidences of fibroadenomas and adenocarcinomas in the mammary gland in all treated groups. UPA exposure [AUC(0-24h)] at the highest dose in rats was 67 times human therapeutic exposure at 10 mg/day. In mice, no tumor of any type increased at UPA exposures up to 313 times of therapeutic exposure. UPA-related findings in mice were limited to organ weight changes in the liver, pituitary, thyroid/parathyroid glands, and epididymis as well as minimal panlobular hepatocellular hypertrophy in male and female mice receiving 130 mg/kg/day. Rats had UPA-related non-neoplastic findings in the reproductive system (mammary gland, ovary, uterus, vagina, seminal vesicle, prostate), endocrine system (adrenal, pituitary), thymus, muscle, liver, pancreas and lungs most of which are considered to be due to exaggerated pharmacological action of the compound.

Emergency Contraception

There have been numerous attempts to control fertility after unprotected sexual intercourse (UPSI). From very bizarre methods like the vaginal application of Coca Cola to the more serious attempts using calcium antagonists influencing fertility parameters in sperm to hormonal methods or intrauterine devices. So far, hormonal methods preventing or delaying ovulation have proved to be the most popular starting with the combination of ethinyl estradiol and levonorgestrel (LNG), known as the Yuzpe regimen. The first dose had to be taken within 72 hours of UPSI, a second one 12 hours later. Later on, LNG alone, at first in a regimen similar to the Yuzpe method (2 × 0.75 mg 12 hours apart) showed to be more successful, eventually resulting in the development of a 1.5 mg LNG pill that combined good efficacy with a high ease of use. Several efficacious and easy to use methods for emergency contraception (EC) are available on the market today with the most widely spread being LNG in a single dose of 1.5 mg (given as one tablet of 1.5 mg or 2 tablets of 0.75 mg each) for administration up to 3 days (according to WHO up to 5 days) after UPSI. Its limitations are the non-optimal efficacy which is decreasing the later the drug is taken and the fact that it is only approved for up to 72 hours after UPSI. This regimen has no effect on the endometrium, corpus luteum function and implantation, is not abortive and don't harm the fetus if accidentally taken in early pregnancy. It has no impact on the rate of ectopic pregnancies. It has become the standard method used up to this day in most countries. Since the mid 1970s copper IUDs have been used for EC, which show a high efficacy. Their disadvantages lie in the fact that EC is considered an off label use for most IUDs (not for the GynFix copper IUD in the European Union) and that they might not be acceptable for every patient. Furthermore IUD-insertion is an invasive procedure and it is required trained providers and sterilized facilities. Mifepristone in the dosages of 10 or 25 mg is used with good results as an emergency contraceptive in China for up to 120 hours after UPSI, but has never received any significant consideration in Western countries. While high doses of mifepristone has an effect on endometrial receptivity and will inhibit ovulation if given in the follicular phase and prevent implantation if given in the early luteal phase, low doses such as 10 mg has no impact on the endometrium. Mifepristone does not increase the rate of ectopic pregnancies. The most recent development is the approval of the selective progesterone receptor modulator ulipristal acetate (UPA) in the dosage of 30 mg for EC up to 5 days after UPSI, combining the safe and easy application of the single dose LNG pill with an even higher efficacy. It has shown to be more efficacious than LNG and can be used for up to 120 hours after UPSI; the difference in efficacy is highest for 0–24 hours, followed by 0–72 hours following UPSI. No VTE has been reported following UPA-administration or any progesterone receptor modulator. No effect on endometrium, corpus luteum function and implantation has been observed with doses used for EC. Independent of the substance it should be noted that, if there is a choice, the intake of an oral emergency contraceptive pill should happen as soon as possible after the risk situation. A preexsisting pregnancy must be excluded. Possible contraindications and drug interactions must be considered according to the individual special product informations.