Progesterone Receptor Modulators Research Articles

Transcriptomic Profile of Breast Tissue of Premenopausal Women Following Treatment with Progesterone Receptor Modulator: Secondary Outcomes of a Randomized Controlled Trial.

Progesterone receptor antagonism is gaining attention due to progesterone's recognized role as a major mitogen in breast tissue. Limited but promising data suggest the potential efficacy of antiprogestins in breast cancer prevention. The present study presents secondary outcomes from a randomized controlled trial and examines changes in breast mRNA expression following mifepristone treatment in healthy premenopausal women. We analyzed 32 paired breast biopsies from 16 women at baseline and after two months of mifepristone treatment. In total, 27 differentially expressed genes were identified, with enriched biological functions related to extracellular matrix remodeling. Notably, the altered gene signature induced by mifepristone in vivo was rather similar to the in vitro signature. Furthermore, this gene expression signature was linked to breast carcinogenesis and notably linked with progesterone receptor expression status in breast cancer, as validated in The Cancer Genome Atlas dataset using the R2 platform. The present study is the first to explore the breast transcriptome following mifepristone treatment in normal breast tissue in vivo, enhancing the understanding of progesterone receptor antagonism and its potential protective effect against breast cancer.

Ulipristal (UPA) effects on rat ovaries: Unraveling follicle dynamics, ovulation inhibition, and safety implications for prolonged use

Ulipristal (UPA), a selective progesterone receptor modulator, has both agonistic and antagonistic effects on progesterone receptors. UPA suppresses ovulation by inhibiting the luteinizing hormone (LH) surge from the pituitary gland; however, the direct effect of UPA on ovarian tissue remains poorly studied. In the present study, we examined the effects of UPA on the ovaries of rats. Rats were treated for 28 days with UPA, and the effects of UPA on ovarian tissue were examined histologically and the expression of antioxidant genes and cell death markers were also investigated. UPA treatment increased the number of primordial follicles at each treatment group, primordial follicles increased at all dose levels, but the size/magnitude of the effect decreased with the increasing dose. The number of primary and antral follicles tended to increase with increasing UPA levels. Furthermore, the decrease in primary follicle number could be attributed to the exhaustion of follicles, but the examination of proliferation markers, oxidative stress markers, and cell death markers revealed no remarkable toxic effects on ovarian tissues. These results suggest that UPA treatment promotes follicle development at each stage but inhibits ovulation by suppressing the LH surge, resulting in an increase in atretic follicles or unruptured luteinized cysts. These results suggest that UPA may not have both toxic effects on the ovary and a direct local effect on ovarian follicles, but we should be careful about the effects of prolonged UPA treatment in patients with uterine fibroids on their future fecundity.

To Evaluate the Efficacy and Safety of Mifepristone in Reducing the Size & Symptoms of Uterine Leiomyoma/Fibroids.

Uterine leiomyomas, or fibroids, are prevalent benign gynecological tumors affecting many women during their reproductive years. While surgical excision has long been the gold standard for fibroid treatment, the pharmacological management, including progesterone receptor modulators like mifepristone (RU 486), has garnered attention due to the reduced surgical approaches. However, there is a notable paucity of research on the effectiveness of mifepristone, on the same. This study seeks to evaluate the safety and efficacy of mifepristone in reducing uterine leiomyoma size and alleviating associated symptoms. Conducted prospectively, the study enrolled 20 pre-menopausal women, aged 18years or older, from Nanavati Max Super Speciality Hospital Mumbai, Maharashtra, India. Participants were selected based on specific inclusion criteria, including the presence of at least one uterine myoma with a minimum diameter of 2.5cm as confirmed by ultrasound. Participants had an average age of 39.75years and an average BMI of 27.58kg/m2. The study found that mifepristone significantly reduced uterine volume by 75%, with hemoglobin levels substantially improving from 9 gm/dL initially to 12.51 gm/dL after six months. Pain intensity, assessed using the Visual Analog Scale (VAS) score, gradually decreased from baseline to three-month, with all 20 patients reporting the complete absence of pelvic pain by six months. This prospective study highlights mifepristone's promise as a non-surgical approach to effectively reduce uterine fibroid volume, improve hemoglobin levels, and mitigate uterine blood loss in patients.

White matter volume and treatment with selective progesterone receptor modulator in patients with premenstrual dysphoric disorder

Premenstrual dysphoric disorder (PMDD) is a mood disorder for which selective progesterone receptor modulator (SPRM) treatment has been demonstrated to be beneficial. The neural signatures of this treatment have been so far identified as greater fronto-cingulate reactivity during aggressive response to provocation, but no changes in terms of gray matter structure. White matter has recently been found to differ between patients with PMDD and healthy controls. The present study thus sought to investigate the relationship between white matter volume and SPRM treatment in patients with PMDD. A pharmaco-neuroimaging study was conducted on patients with PMDD participating in a randomized controlled trial. Participants underwent magnetic resonance imaging before and after treatment randomization to ulipristal acetate (an SPRM), or placebo, for three months. The interaction effect of treatment by time on white matter volume (WMV) was assessed. Voxel based morphometry analyses were performed on both a whole brain exploratory level and on regions of interest. No treatment effect was observed on WMV in any region, including the anterior thalamic radiations, cingulum, forceps minor, fornix, inferior fronto-occipital fasciculus, superior cerebellar peduncle, superior longitudinal fasciculus, and uncinate fasciculus. This is the first finding to indicate that no white matter volume alterations follow three-month progesterone antagonism, suggesting that white matter volume does not participate in symptom relief upon SPRM treatment for PMDD.

Hydroboration of vinylsilanes providing diversity-oriented hydrophobic building blocks for biofunctional molecules.

Hydroboration of vinylsilanes with BH3 affords two silylethanol regioisomers. Herein, we investigated the regioisomeric ratio of hydroboration products from various vinylsilanes, focusing on the characteristic reaction profile. All investigated vinylsilanes afforded both regioisomers, and greater bulkiness increased the proportion of the Markovnikov products. The obtained silylethanols were used as hydrophobic building blocks for constructing nuclear progesterone receptor (PR) modulators. Notably, structural conversions from an α-isomer (silylethan-1-oxy derivative) to a β-isomer (2-silylethoxy derivative) caused complete activity-switching from a PR agonist to an antagonist. Our results indicate that silylethanols are useful for structural development, and vinylsilanes are a versatile source of hydrophobic building blocks for obtaining biofunctional molecules.

Future Directions to Explore to Develop Ideal Anti-Cancer Progesterone Receptor Modulators

Future Directions to Explore to Develop Ideal Anti-Cancer Progesterone Receptor Modulators

Ulipristal acetate, a selective progesterone receptor modulator, induces cell death via inhibition of STAT3/CCL2 signaling pathway in uterine sarcoma

Ulipristal acetate (UPA) is a selective progesterone receptor modulator and is used for the treatment of uterine leiomyoma (a benign tumor). Uterine sarcoma which is highly malignant cancer with a poor prognosis is clinically resembled with uterine leiomyoma. There has been no experimental research on the effect of UPA on uterine sarcoma. In this study, we examined the efficacy of UPA in uterine sarcoma with in vitro and in vivo animal models. Cytotoxicity of UPA was determined in uterine sarcoma cell lines (MES-SA, SK-UT-1, and SK-LMS-1). Apoptotic genes and signaling pathways affected by UPA were analyzed by complementary DNA (cDNA) microarray of uterine sarcoma cell lines and western blot, respectively. An in vivo efficacy of UPA was examined with uterine sarcoma cell line- and patient-derived xenograft (PDX) mice models. UPA inhibited cell growth in uterine sarcoma cell lines and primary culture cells from a PDX mouse (PDX-C). cDNA microarray analysis revealed that CCL2 was highly down-regulated by UPA. Phosphorylation and the total expression of STAT3 were inhibited by UPA. UPA also inhibited CCL2 and STAT3 in PDX-C. The inhibitory effect of UPA had not changed in the overexpression of PR and treatment of progesterone. In vivo efficacy studies with cell line-derived xenografts and a PDX model with leiomyosarcoma, a typical uterine sarcoma, demonstrated that UPA significantly decreased tumor growth. UPA had significant anti-tumor effects in uterine sarcoma through the inhibition of STAT3/CCL2 signaling pathway and might be a potential therapeutic agent to treat this disease.

The efficacy of medical management of leiomyoma-associated heavy menstrual bleeding: a mini review

Leiomyomas, or fibroids, are benign uterine tumors that are commonly associated with abnormal uterine bleeding-L particularly heavy menstrual bleeding (HMB). Treatment options include expectant, medical, image-guided, and surgical. Medical management of HMB is the preferred first-line treatment and includes nonsteroidal anti-inflammatory drugs, contraceptive hormones, tranexamic acid, levonorgestrel intrauterine system, gonadotropin-releasing hormone (GnRH) antagonists and antagonists, selective progesterone receptor modulators, selective estrogen receptor modulators, and aromatase inhibitors. Although alternatives such as vitamins and supplements have been suggested, there is currently a lack of robust evidence of their efficacy. Many of these therapies treat the symptoms rather than the underlying pathology. Progestin-based therapies are the most commonly utilized, although research supporting their effectiveness in the treatment of HMB is modest. Although GnRH agonists and antagonists, which are federal drug administration-approved therapies, provide substantial improvement in abnormal uterine bleeding-L with HMB, the effects typically last for the duration of therapy. Patients may also face financial barriers to GnRH analog therapy. Future studies are required to delineate the nonhormonal treatment options and the long-term management of leiomyoma-associated HMB.

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.

Clinical Efficacy, Pharmacokinetics, and Safety of the Available Medical Options in the Treatment of Endometriosis-Related Pelvic Pain: A Scoping Review.

In this scoping review, we sought to identify published studies evaluating the drugs currently used in the treatment of endometriosis-related pelvic pain, with reflection on their chemical properties, pharmacokinetics, safety profile, and clinical efficacy. A literature search was conducted with the use of the PubMed and EMBASE electronic databases, focusing on identifying articles published in English between January 1990 and 2023. Based on the included studies, current therapy options for the treatment of endometriosis-related pain identified and reviewed in this article were: (1) non-steroidal anti-inflammatory drugs; (2) combined oral contraceptive (COCs); (3) progestins; (4) gonadotropin-releasing hormone agonists and antagonists; (5) aromatase inhibitors (AIs); (6) selective estrogen and progesterone receptor modulators; and (7) levonorgestrel-intrauterine device. Based on the published evidence, clinicians should consider NSAIDs, COCs, and progestins as the first-line medical therapies. Compared with second-line options, such as GnRH agonists/antagonists or AIs, the abovementioned first-line options are well tolerated, efficacious, and exhibit lower overall price. Future research priorities should be to identify novel target therapies and to evaluate the effects of available drugs through different routes of administration.

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.

Next step in the development of mesoprogestins: the preclinical profile of EC313.

The pharmacological target for progesterone, different progestins, and Selective Progesterone Receptor Modulators (SPRMs) is the nuclear progesterone receptor (PR). EC313 is a new member of a subgroup of SPRMs, mesoprogestins, which combine especially PR- agonistic and PR-antagonistic activities in one molecule. The suitable in vivo-model for the differentiation of SPRMs from the subgroup of mesoprogestins is the estrogen-primed juvenile rabbit endometrium assay (McPhail Assay). Remarkably, in contrast to other well-known SPRMs with no agonistic effects in this test, EC313 shows clear partial PR-agonistic effects that are higher than that of the well-known mesoprogestin Asoprisnil which already demonstrated remarkable clinical effectiveness for the treatment of uterine fibroids and endometriosis. The findings from the guinea pig studies presented here can be the impetus for further preclinical development of EC313. This model shows the same features for the termination of pregnancy by antiprogestins such as Mifepristone and Ulipristal acetate (UPA) in humans. Moreover, it is possible to distinguish between progestational and anti-progestational activities in the same experiment. The EC313 treatment reveals PR dominance in the genital tract and inhibits unopposed estrogenic effects. In very high doses (30.0 mg/animal/day subcutaneously (s.c.)) given twice on pregnancy days 43 and 44, no premature labor was induced (in contrast to UPA, dosed at 10.0 and 30. mg/animal/day s.c.). The anti-ovulatory activity of EC313 exceeds that of Ulipristal acetate or Mifepristone. EC313 binds to the steroid receptors in vitro with a similar affinity as the natural ligand progesterone. At the glucocorticoid receptor (GR) EC313 acts as a weak inhibitor. Minor activities at the human androgen receptor (AR) and mineralocorticoid receptor (MR) are considered negligible. No binding to the estradiol receptor was detected. In contrast to some in vitro-receptor findings, estrogenic, anti-estrogenic, androgenic, anti-androgenic, glucocorticoid, and anti-glucocorticoid actions were absent in vivo. The tissue selectivity of EC313 was demonstrated previously by reducing the growth and proliferation of uterine fibroids in animal models (lowest effective dosage 0.1 mg/kg/day s.c.).. As shown in this article, the anti-fibroid activity of EC313 was confirmed with a 10 times lower dosage (0.01 mg/kg/day s.c.). It was also shown that EC313 reduces the growth of endometriotic lesions in a human xenograft immune-deficient (NOD-SCID) mice model with a comparatively very low dosage range. In the aforementioned EC313 activity model, UPA was tested as the reference compound, the clinical effectiveness of which has already been demonstrated. For an explanation of these findings, the possibility is discussed that the mixed agonistic/antagonistic feature of EC313 is tissue target-specific based on its super-additive synergism characteristic for active bifunctional agents. In conclusion, the specific pharmacodynamic profile of this compound opens the possibility for the development of a drug with a distinct pharmaco-endocrinological profile against uterine fibroids, endometriosis, and other PR-dependent gynecological diseases.

Progesterone control of myometrial contractility

During pregnancy, the primary function of the uterus is to be quiescent and not contract, which allows the growing fetus to develop and mature. A uterine muscle layer, myometrium, is composed of smooth muscle cells (SMCs). Before the onset of labor contractions, the uterine SMCs experience a complex biochemical and molecular transformation involving the expression of contraction-associated proteins. Labor is initiated when genes in SMCs are activated in response to a combination of hormonal, inflammatory and mechanical signals. In this review, we provide an overview of molecular mechanisms regulating the process of parturition in humans, focusing on the hormonal control of the myometrium, particularly the steroid hormone progesterone. The primary reason for discussing the regulation of myometrial contractility by progesterone is the importance of the clinical problem of preterm birth. It is thought that the hormonal mechanisms regulating premature uterine contractions represent an untimely triggering of the normal events occurring during term parturition. Yet, our knowledge of the complex and redundant hormonal pathways controlling uterine contractile activity leading to delivery of the neonate remains incomplete. Finally, we introduce recent animal studies using a novel class of drugs, Selective Progesterone Receptor Modulators, targeting progesterone signaling to prevent premature myometrial contractions.

GABA-ergic Modulators: New Therapeutic Approaches to Premenstrual Dysphoric Disorder.

Premenstrual dysphoric disorder (PMDD) is characterized by the predictable onset of mood and physical symptoms secondary to gonadal steroid fluctuation during the luteal phase of the menstrual cycle. Although menstrual-related affective dysfunction is responsible for considerable functional impairment and reduction in quality of life worldwide, currently approved treatments for PMDD are suboptimal in their effectiveness. Research over the past two decades has suggested that the interaction between allopregnanolone, a neurosteroid derivative of progesterone, and the gamma-aminobutyric acid (GABA) system represents an important relationship underlying symptom genesis in reproductive-related mood disorders, including PMDD. The objective of this narrative review is to discuss the plausible link between changes in GABAergic transmission secondary to the fluctuation of allopregnanolone during the luteal phase and mood impairment in susceptible individuals. As part of this discussion, we explore promising findings from early clinical trials of several compounds that stabilize allopregnanolone signaling during the luteal phase, including dutasteride, a 5-alpha reductase inhibitor; isoallopregnanolone, a GABA-A modulating steroid antagonist; and ulipristal acetate, a selective progesterone receptor modulator. We then reflect on the implications of these therapeutic advances, including how they may promote our knowledge of affective regulation more generally. We conclude that these and other studies of PMDD may yield critical insight into the etiopathogenesis of affective disorders, considering that (1) symptoms in PMDD have a predictable onset and offset, allowing for examination of affective state kinetics, and (2) GABAergic interventions in PMDD can be used to better understand the relationship between mood states, network regulation, and the balance between excitatory and inhibitory signaling in the brain.

Targeting nuclear hormone receptors for the prevention of breast cancer.

Advancements in research have led to the steady decline of breast cancer mortality over the past thirty years. However, breast cancer incidence has continued to rise, resulting in an undue burden on healthcare costs and highlighting a great need for more effective breast cancer prevention strategies, including targeted chemo preventative agents. Efforts to understand the etiology of breast cancer have uncovered important roles for nuclear receptors in the development and progression of breast cancer. Targeted therapies to inhibit estrogen receptor (ER) and progesterone receptor (PR) signaling (selective ER modulators, aromatase inhibitors and selective PR modulators) have shown great promise for the treatment and prevention of hormone receptor (HR)-positive breast cancer. However, these drugs do not prevent HR-negative disease. Therefore, recent efforts have focused on novel targeted therapies with the potential to prevent both HR-positive and HR-negative breast cancer. Among these include drugs that target other nuclear receptors, such as retinoic acid receptor (RAR), retinoid X receptor (RXR) and vitamin D receptor (VDR). In this review we provide an overview of recent preclinical and clinical trials targeting members of the nuclear receptor superfamily for the prevention of breast cancer.

Efficacy and safety of vilaprisan in women with uterine fibroids: data from the ASTEROID 3 randomized controlled trial

Vilaprisan is a highly potent selective progesterone receptor modulator shown to reduce heavy menstrual bleeding, induce amenorrhea, and diminish uterine fibroid volume in phase 2 studies. The objective of ASTEROID 3 was to demonstrate the superiority of vilaprisan compared with placebo in the treatment of heavy menstrual bleeding in women with uterine fibroids. Randomized, double-blind, placebo-controlled, multicenter phase 3 study. Hospitals and medical centers. Women with ≥1 uterine fibroid of ≥3 cm and heavy menstrual bleeding of >80 mL/cycle. Women were randomly assigned to 1 of 4 treatment arms, which were planned to comprise 2 treatment periods of 12 weeks, each with vilaprisan (2 mg/d) or placebo that were continuous or separated by a break of one bleed. Amenorrhea (primary end point; <2 mL in the last 28 days of treatment) and heavy menstrual bleeding response (key secondary end point; <80 mL/cycle and >50% reduction in bleeding from baseline) were measured with the alkaline hematin method. Change in volume of the 3 largest fibroids from baseline to end of treatment was assessed by ultrasound. Safety was monitored throughout the study. Overall, 75 women completed the first 12 weeks of treatment. Statistically significant and clinically meaningful differences were observed between the vilaprisan- and placebo-treated groups in both the full analysis and per-protocol sets. In the per-protocol set (n = 36 and n = 12 for the vilaprisan and placebo groups, respectively), amenorrhea was observed more frequently in women treated with vilaprisan than in those who received placebo (83.3% vs. 0%, P<.0001), with a median time to onset of 3 days in the vilaprisan group. Similarly, more vilaprisan- than placebo-treated women achieved a response in heavy menstrual bleeding (91.7% vs. 25.0%, P<.0001). Serious adverse events were reported for 22 (27.8%) of 79 women and were evenly distributed among the 4 groups receiving vilaprisan and/or placebo. None of these events led to study discontinuation or were related to the liver, and no new safety findings were identified compared with the earlier phase 2 ASTEROID studies. Vilaprisan is efficacious and well tolerated over 12 weeks in the treatment of heavy menstrual bleeding associated with uterine fibroids. Further investigations of the long-term efficacy and safety of vilaprisan are warranted. NCT03400943 (ClinicalTrials.gov).

Mifepristone: effect on PBMC receptivity in healthy women and women with endometrial hyperplastic processes

In our previous study we found that peripheral blood mononuclear cells (PBMC) at women with endometrial proliferative processes increase their sensitivity to the suppressing action of sex steroid hormones. In order to reduce the receptivity of PBMC, it is possible to prescribe hormonal drugs. However, when studying the relative binding activity of the receptors, it was found that the affinity of medroxyprogesterone acetate, norethisterone acetate, in PBMC was 54% and 48% respectively. And research of selective modulators of progesterone receptors is promising.

O-190 Establishment of non-invasive prediction models for diagnosis of the subtypes and tissue composition of uterine leiomyomas by machine learning using MRI data

Abstract Study question We investigated whether machine learning models using MRI data can predict the subtypes and tissue composition of uterine leiomyomas. Summary answer Our machine learning models using MRI data were able to predict the subtypes and tissue composition of uterine leiomyomas with high accuracy. What is known already Recently, somatic mutations in the Mediator complex subunit 12 (MED12) gene were found to be a biomarker of uterine leiomyomas, which is detected in about 70% of uterine leiomyomas. Uterine leiomyomas are classified into two subtypes with or without the MED12 mutation. These subtypes differ in the ratio of smooth muscle cells and fibroblasts and in the amount of collagen fibers. In addition, sensitivities to female hormones differ between smooth muscle cells and fibroblasts. Thus, the effect of therapeutic drugs (GnRH analogs and selective progesterone receptor modulators) may differ depending on the subtypes and tissue composition of uterine leiomyomas. Study design, size, duration We analyzed 90 uterine leiomyoma nodules (MED12 mutation-positive and negative = 62 and 28) obtained from 51 women who underwent surgery at our hospital between 2020 and 2022. Seventy-one uterine leiomyomas (MED12 mutation-positive and negative = 49 and 22) were assigned to the primary dataset to establish the prediction models. Nineteen uterine leiomyomas (MED12 mutation-positive and negative = 13 and 6) were assigned to the test dataset to validate the prediction model utility. Participants/materials, setting, methods For each leiomyoma, the tumor signal intensity was quantified by five MRI sequences (T2WI, ADC, T1map, T2*BOLD, MTC) for evaluating the collagen amount. After surgery, genotyping of MED12 was examined and Trichrome staining was performed to quantify the collagen amount. Using these results, we established the prediction models based on machine learning by applying support vector classification and logistic regression for subtype prediction, and support vector regression and Ridge regression for tissue composition prediction. Main results and the role of chance The signal intensity of all five MRI sequences differed significantly between the subtypes. The cross-validation within the primary dataset showed that support vector classification and logistic regression models using five MRI sequences and MED12 genotyping data were highly predictive of the subtypes (AUC: 0.984 and 0.995, respectively). The validation using the test dataset showed that both models were able to predict the subtypes for all uterine leiomyomas (AUC: 1.000, both). This result showed higher accuracy than each MRI sequence’s cut-off value alone. On the other hand, four MRI sequence values (other than ADC) showed a significant correlation with the collagen amount. However, to improve accuracy, we added the ADC data and the result of the subtype predicted by the preceding models to the predictors for the collagen amount. Support vector regression and Ridge regression models using five MRI sequences and Trichrome staining data were shown to be highly predictive of the collagen amount in cross-validation within the primary dataset (R2: 0.570 and 0.525, respectively) and in validation using the test dataset (R2: 0.648 and 0.675, respectively). Moreover, the prediction models using only T2WI and ADC, which are taken in general clinical practice, were as accurate as using five MRI sequences. Limitations, reasons for caution In this study, we used limited data by using one specific MRI machine in a single center to establish the prediction models. We have not verified that similar results would be obtained under different conditions. Therefore, further training and evaluation in larger cohorts are required for clinical use. Wider implications of the findings The prediction models established in this study may be useful in clinical support such as predicting the effect of drug therapy and selecting therapeutic drugs, such as GnRH analogs and selective progesterone receptor modulators. Their utilities will be confirmed by validation using our prediction models in studies involving drug therapy. Trial registration number not applicable

P-356 establishment of a novel 3D spheroid culture system of uterine leiomyoma cells

Abstract Study question To establish three-dimensional (3D) spheroid culture system of uterine leiomyoma (ULM) cells that responds to estrogen(E) and progesterone(P). Summary answer We established the 3D spheroid culture system of ULM cells, in which the ULM-spheroid grows in response to progesterone. What is known already ULMs proliferate in response to female hormones in the patients-derived xenograft model in vivo. However, it is controversial whether ULM cells proliferate in response to female hormones in in vitro monolayer culture system. We reported that ULM cells formed nodule-like aggregates of cells when the cells were grown in 3D culture using collagen gel. However, 3D spheroid culture system of ULM cells is not established yet. Recently, somatic mutations in the MED12 gene were detected in almost 70% of ULMs. It is also unclear whether responsiveness of ULM cells to female hormones differs between MED12-mutation positive and negative ULMs. Study design, size, duration Fourteen and 13 ULMs obtained from 18 premenopausal women were used for monolayer culture and 3D spheroid culture, respectively. The isolated ULM cells were confirmed to be smooth muscle cells with 80% purity and to have progesterone receptors by immunocytochemistry. The cells were preincubated for 2 days and then used for the following experiments below. MED12-mutation status was analyzed by Sanger sequencing. Monolayer and spheroid cultures were done on MED12-mutation positive and negative ULM cells. Participants/materials, setting, methods For the monolayer culture system, cells were incubated with E+P, E alone, P alone, and control (without E+P) for 7 days. For 3D culture system, cells were incubated in the low attachment well dish to induce floating cell culture, and after 24 h, we identified the floating cell aggregates as spheroid of ULM cells. Then, the ULM-spheroids were incubated with E+P, E alone, P alone, E+P+selective progesterone receptor modulator (SPRM), and control for 7 days. Main results and the role of chance Responsiveness to female hormones was assessed by counting cells for monolayer culture, and by measuring the cross-sectional area of the spheroid for 3D culture system. ULM cells did not proliferate by any female hormones in the monolayer culture system. In the 3D spheroid culture system, the ULM-spheroid cells showed expression of alpha-smooth muscle actin and vimentin, indicating that most of the spheroid cells are smooth muscle cells. In MED12-mutation negative ULMs, the mean of the cross-sectional area of the spheroid of E+P , P alone, E alone, E+P+SPRM and control were 0.375mm², 0.343mm², 0.237mm², 0.252mm² and 0.193mm², respectively, while in MED12-mutation positive ULMs, the area were 0.349mm², 0.338mm², 0.268mm², 0.264mm². and 0.215mm². The morphology of the spheroid of the E alone, E+P+SPRM and control groups showed the loss of smooth muscle cells. These results suggest that the growth of the ULM-spheroid is maintained by progesterone, and that the responsiveness of the spheroid to progesterone does not differ between MED-mutation negative and positive ULM cells. Our study showed that ULM cells of the 3D spheroid culture system acquire function to respond to progesterone. Limitations, reasons for caution Further studies are needed to investigate whether the 3D spheroid culture system established in this study accurately reflects the responsiveness to female hormones of the in vivo. Wider implications of the findings Our study showed that the 3D spheroid culture system of ULM cells has the responsiveness to progesterone whereas the monolayer culture system does not. The 3D spheroid culture system of ULM cells established in this study would be useful as a screening system for therapeutic agents. Trial registration number non-clinical trials

The use of a short course of Ulipristal Acetate for acute abnormal uterine bleeding in women without uterine fibroids.

Ulipristal Acetate (UPA) is a synthetic selective progesterone receptor modulator. It is used as emergency contraception and to reduce pain and blood loss in women of reproductive age with uterine fibroids. The first mechanism of action is myometrial apoptosis, the second is on the hypo-thalamic-pituitary-ovarian axis and the third action, is an anti-proliferative effect on the endometrium. Mainly based on the latter two, UPA is increasingly used off-label in women with abnormal uterine bleeding (AUB) without fibroids. The aim of this paper is to find evidence for a short course of UPA to treat acute AUB without fibroids, performing a systematic review as well as scrutinising literature data on the pharmacokinetics and on short term bleeding control in women with fibroids. A systematic electronic literature review was performed in February 2022. Inclusion criteria were UPA administered to women without myomas in a setting of acute uterine bleeding. Further criteria included papers describing early bleeding control using UPA, deemed independent of the presence of fibroids, with specific attention to the median time to amenorrhoea. The main outcome measured was the bleeding control within 10 days. One case report was identified. The data on symptomatic women with fibroids using 5 mg or 10 mg daily revealed bleeding control was reported within 10 days in 81% and 89% respectively, with amenorrhoea in 57% and in 78% respectively. A short-term administration may prove effective in abnormal uterine bleeding irrespective of the presence of uterine fibroids. However, more randomised controlled trials are needed and should be performed before implementation in general clinical practice. A short course of Ulipristal acetate as promising treatment for acute uterine bleeding without fibroids.