Mifepristone Treatment Research Articles

Success of medication abortion with mifepristone followed by two doses of misoprostol in very early pregnancy

ObjectiveTo compare medication abortion (MAB) success in very early pregnancy (VEP) with mifepristone followed by either one or two doses of misoprostol. Study DesignWe performed a retrospective cohort analysis of VEP MABs from 7/1/2021 to 05/31/2022 treated with mifepristone 200mg oral followed by a single dose of misoprostol 800mcg buccal 24-48 hours later and MABs from 06/21/2022 to 10/31/2022 treated with mifepristone 200mg oral followed by two doses of misoprostol 800mcg buccal spaced four hours apart, with first dose taken 24-48 hours after mifepristone. Serum BhCG was collected at the time of mifepristone treatment with additional BhCG collected 48-72 hours after misoprostol treatment in both groups. Success was defined as a BhCG decline of > or = 50%. MAB failure was defined as ongoing, viable pregnancy determined by follow up ultrasound or procedural intervention with aspiration. ResultsThere were 423 patients in the single dose misoprostol group and 262 patients in the two-dose misoprostol group. There were no significant differences between the two groups in baseline characteristics. In the single dose group, 372 (87.9%) were treated successfully; in the two-dose group, 224 (85.5%) were treated successfully. There was no significant difference in MAB success between the groups (p=0.73). ConclusionThe addition of a second dose of misoprostol does not improve the success of MAB in VEP. Clinical Trial Registration NumberN/A

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.

Safety and Efficacy of Oral Mifepristone for Cervical Ripening and Induction of Labor.

Background Labor induction, a common practice to prevent maternal and fetal complications from prolonged labor, involves stimulating contractions before they begin naturally. This can be achieved through medications, mechanical methods, or surgical interventions. Cervical ripening is crucial for successful delivery. When the cervix is not sufficiently ripe, drugs are often used to augment this process chemically. Objective To evaluate the safety and efficacy of mifepristone for cervical ripening and induction of labor. Method A sample size of 200 was used in this single-blind randomized control trial. Primarily, pregnant women with term pregnancies, Bishop scores <6, and cephalic fetal presentation were included in the study. The study population was randomly divided into test and control groups. The test group (n=100) was administered 200 mg of mifepristone orally, while the control group (n=100) received a placebo. The Bishop score was reassessed 24 hours after mifepristone administration. Patients were taken for labor induction if their Bishop score was >6. For individuals with a Bishop score of <6, 1 mg of dinoprostone gel was administered intracervically once every six hours. Safety and efficacy were assessed by analyzing several parameters associated with labor progression, maternal outcomes, and fetal outcomes. Results The mean age of patients in the test group was 26±4.5 years, while in the control group, it was 26±5 years. The induction-to-delivery interval was notably shorter in the test group (18.8±2.3 hours) than in the control group (19.24±1.8 hours, p<0.0001). After the administration of 200 mg mifepristone, the mean Bishop score in the test group was 5.74±0.8, compared to 5.13±0.76 in the control group. The increase in the Bishop score after mifepristone treatment was significantly higher in the test group than in the control group (p-value=0.013). In the study, 73 (73%) patients in the test group had a normal vaginal delivery (NVD), whereas NVD accounted for 64 (64%) patients in the control group. Instrumental deliveries were less frequent in the test group, accounting for 14 (14%) patients, compared to 16 (16%) patients in the control group. The frequency of lower segment cesarean section (LSCS) was also lower in the mifepristone-treated group at 13 (13%) compared to the control group at 20 (20%). Fetal distress in five (38%) patients and non-progression of labor in 11 (55%) patients were the most frequent indications for LSCS in the test and control groups, respectively. There was no significant difference in neonatal outcomes between the test and control groups. Meconium-stained liquor was the most frequent complication in both the test group(10, 10%) and the control group (5, or 5%). Conclusion Administration of mifepristone effectively increased the Bishopscores and reduced the induction-to-delivery interval compared to controls, highlighting its potential as a cervical ripening agent.

Local vaginal bioelectrical impedance can predict preterm delivery in mice.

Preterm birth is a serious pregnancy complication that affects neonatal mortality, morbidity, and long-term neurological prognosis. Predicting spontaneous preterm delivery (PTD) is important for its management. While excluding the risk of PTD is important, identifying women at high risk of PTD is imperative for medical intervention. Currently used PTD prediction parameters in clinical practice have shown high negative predictive values, but low positive predictive values. We focused on sulfated and sialylated glycocalyx changes in the uterus and vagina prior to the onset of parturition and explored the potential of electrophysiological detection of these changes as a PTD prediction parameter with a high positive predictive value. In vivo local vaginal bioelectrical impedance (VZ) was measured using two different mouse PTD models. PTD was induced in ICR mice through the subcutaneous injection of mifepristone or local intrauterine injection of lipopolysaccharide (LPS). The PTD rates were 100% and 60% post-administration of mifepristone (16-20 h, n = 4) and LPS (12-24 h, n = 20), respectively. The local VZ values (15 and 10 h after mifepristone or LPS treatment, respectively) were significantly lower in the PTD group than in the non-PTD group. Receiver operator characteristic (ROC) curve analysis of VZ at 125 kHz as a predictor of PTD showed an area under the ROC curve of 1.00 and 0.77 and positive predictive values of 1.00 and 0.86, for the mifepristone and LPS models, respectively, suggesting that local VZ value can predict PTD. Histological examination of the LPS-treated model 6 h post-treatment revealed increased expression of sulfomucins and/or sulfated proteoglycans and sialomucins in the cervical epithelium, cervical stroma and vaginal stroma. In conclusion, local VZ values can determine sulfated and sialylated glycocalyx alterations within the uterus and vagina and might be a useful PTD prediction parameter.

Proteomic analysis of central amygdala systems regulated by the glucocorticoid receptor antagonist mifepristone in the context of alcohol dependence

Alcohol use disorder (AUD) is a chronic psychiatric disorder characterized by escalated alcohol use and emergence of negative emotional states during withdrawal. Studies show a dysregulation of glucocorticoid signaling in AUD, affecting the hypothalamic-pituitary-adrenal (HPA) axis and the central amygdala (CeA). Excessive activation of glucocorticoid receptors (GRs) is hypothesized to promote cognitive dysfunction, negative emotional states, and escalated drinking. Previous work demonstrates a functional increase in GR activity in the CeA during alcohol withdrawal in alcohol-dependent animal models. Importantly, the GR antagonist mifepristone reduces alcohol-seeking and drinking behaviors in rodents and humans. The aims of this study were to determine differential CeA protein expression in alcohol-dependent rats and examine the effects of mifepristone treatment. We hypothesized that male and female rats will show sex differences in their CeA protein expression and that alcohol-induced reductions in brain anti-stress signaling (e.g., endocannabinoid system) will be normalized by mifepristone treatment. Male and female Wistar rats were exposed to chronic intermittent ethanol vapor (CIEV) or air (control) for 10 weeks. In week 7, half of each group received subcutaneous placebo pellets while the other half received mifepristone pellets (150mg, 21-day slow release). At the end of Week 10, the rats were sacrificed during acute (6-hour) CIEV withdrawal (and identical time in control groups). The CeA was analyzed using proteomics and ingenuity pathway analysis (IPA). In males, a total of 3050 proteins were detected in the CeA. Of these, 142 proteins were altered by alcohol (but not mifepristone), whereas an additional 253 proteins were altered by alcohol and “normalized” by mifepristone. In females, among the 2632 detected proteins, 46 were affected by alcohol (but not mifepristone), and 25 were altered by alcohol and restored by mifepristone. IPA revealed significant changes in canonical pathways, including the endocannabinoid neuronal synapse pathway and oxidative phosphorylation, affected by alcohol but normalized by mifepristone. Future studies will incorporate alcohol self-administration procedures in male and female rats to functionally examine proteins within these pathways as promising “druggable” targets that offer novel therapeutic avenues for AUD. Supported by NIH-NIAAA R01AA025996, P60AA009803, T32AA007577. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of glucocorticoid blockade on inflammatory responses to acute sleep fragmentation in male mice.

The association between sleep and the immune-endocrine system is well recognized, but the nature of that relationship is not well understood. Sleep fragmentation induces a pro-inflammatory response in peripheral tissues and brain, but it also activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing glucocorticoids (GCs) (cortisol in humans and corticosterone in mice). It is unclear whether this rapid release of glucocorticoids acts to potentiate or dampen the inflammatory response in the short term. The purpose of this study was to determine whether blocking or suppressing glucocorticoid activity will affect the inflammatory response from acute sleep fragmentation (ASF). Male C57BL/6J mice were injected i.p. with either 0.9% NaCl (vehicle 1), metyrapone (a glucocorticoid synthesis inhibitor, dissolved in vehicle 1), 2% ethanol in polyethylene glycol (vehicle 2), or mifepristone (a glucocorticoid receptor antagonist, dissolved in vehicle 2) 10 min before the start of ASF or no sleep fragmentation (NSF). After 24 h, samples were collected from brain (prefrontal cortex, hypothalamus, hippocampus) and periphery (liver, spleen, heart, and epididymal white adipose tissue (EWAT)). Proinflammatory gene expression (TNF-α and IL-1β) was measured, followed by gene expression analysis. Metyrapone treatment affected pro-inflammatory cytokine gene expression during ASF in some peripheral tissues, but not in the brain. More specifically, metyrapone treatment suppressed IL-1β expression in EWAT during ASF, which implies a pro-inflammatory effect of GCs. However, in cardiac tissue, metyrapone treatment increased TNF-α expression in ASF mice, suggesting an anti-inflammatory effect of GCs. Mifepristone treatment yielded more significant results than metyrapone, reducing TNF-α expression in liver (only NSF mice) and cardiac tissue during ASF, indicating a pro-inflammatory role. Conversely, in the spleen of ASF-mice, mifepristone increased pro-inflammatory cytokines (TNF-α and IL-1β), demonstrating an anti-inflammatory role. Furthermore, irrespective of sleep fragmentation, mifepristone increased pro-inflammatory cytokine gene expression in heart (IL-1β), pre-frontal cortex (IL-1β), and hypothalamus (IL-1β). The results provide mixed evidence for pro- and anti-inflammatory functions of corticosterone to regulate inflammatory responses to acute sleep loss.

The Use of Methotrexate and Mifepristone for Treatment of Interstitial Pregnancies: An Overview of Effectiveness and Complications

Interstitial pregnancy is an unusual and potentially life-threatening form of ectopic pregnancy, accounting for approximately 1–6% of all ectopic pregnancies, with a maternal mortality rate of 2–2.5%. Implantation happens in the proximal portion of the fallopian tube as it passes through the myometrium. The resolution of interstitial pregnancy after medical treatment should be assessed by a decline in serum β-hCG, which occurs in about 85–90% of cases. Nonetheless, its effectiveness and consequences have been presented through case reports and case series. However, few cases of interstitial pregnancies treated totally medically with the use of methotrexate and mifepristone have been presented in the literature. Complications of this medical treatments have also never been reviewed before. In the present manuscript, we present a case of interstitial pregnancy treated with methotrexate and mifepristone. The patient after treatment developed a uterine arteriovenous malformation, treated with uterine artery embolization. Furthermore, we performed a systematic review of the literature using Scopus, PubMed and Google Scholar. A total of 186 papers were found, and 7 papers which included 10 cases were assessed for eligibility. The systemic medical treatment with the use of methotrexate and mifepristone was effective in 7 of the 10 cases. Two cases of hemoperitoneum following combined methotrexate and mifepristone treatment were reported. The applicability of this medical conservative treatment should be tailored to the patient, taking into account their obstetric history, gestational age at diagnosis and desire for future pregnancies. Complete resolution after this treatment was achieved in most of the cases reported without major complications. The appearance of uterine arteriovenous malformation can be managed conservatively, and we propose uterine artery embolization as an effective treatment of this rare complication.

The Mechanism of Bushen Zhuyun Prescription in Regulating Luteal Phase Deficiency via Intervention of the Kiss1/GPR54 System in the Hypothalamus

Luteal phase deficiency (LPD) is a significant contributor to infertility and miscarriage. Bushen Zhuyun Prescription (BSZY) is a traditional Chinese medicine formula that has potential to treat LPD. To investigate the effect of BSZY in treating LPD, SD rats with complete estrous cycles were divided into blank, model, dydrogesterone (DYD), high-dose BSZY (BSZY-HD), and low-dose BSZY (BSZY-LD) groups. All the groups were received mifepristone gavage except for the blank group. The pathological changes were observed in the hypothalamus, and the analysis of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone (P), gonadotropin-releasing hormone (GnRH), and cyclic adenosine monophosphate (cAMP) levels in serum. Additionally, the mRNA and their protein expression levels of estrogen receptor α (ERα), ERβ, G protein-coupled receptor 30 (GPR30), kisspeptin 1 (Kiss1), and GPR54 were assessed; and the key molecules expression in cAMP/protein kinase A (PKA) pathway were analyzed. The results revealed that mifepristone treatment caused a decrease in FSH and cAMP levels and an increase in E2 and LH levels, which were normalised in the BSZY treatment groups. The expression of ERα and ERβ mRNA and protein in the hypothalamus was higher in the BSZY groups compared to the blank group. BSZY also resulted in increased expression of Kiss-1, GPR54, and PKA, as well as decreased expression of cAMP-response element binding protein (CREB), c-Fos, phospho-CREB (p-CREB), and p-c-Fos, compared to model group. No significant difference observed in GPR30 expression between the mifepristone and BSZY groups. The mRNA and protein of Kiss1 and GPR54 were decreased in model group and increased after BSZY treatment, while the mRNA and protein expression of PKA, CREB, c-Fos, p-CREB, and p-c-Fos were also decreased significantly. In conclusion, the findings demonstrate that BSZY could effectively regulate hypothalamic ER, interfere with the Kiss1/GPR54 signal transduction system, activate the cAMP/PKA pathway, and regulate key transduction molecules expression of PKA, CREB, c-Fos, there by effecting the level of reproductive hormones and has the potential to treat LPD-related infertility.

The role of mifepristone on first trimester miscarriage treatment – A double-blind randomized controlled trial – MiFirsT

ObjectivesTo evaluate the efficacy of combined mifepristone and misoprostol compared to misoprostol alone in outpatient medical treatment of first trimester miscarriage. Additionally, the study intends to compare the rate of complications, adverse effects, and treatment acceptability between groups. Study DesignSingle-center double-blind randomized placebo-controlled trial including women with diagnosis of missed first trimester miscarriage up to 9 weeks of gestation. ResultsBetween April 2019 and November 2021, 216 women diagnosed with first trimester miscarriage up to 9 weeks of gestation were randomly assigned to mifepristone group or to misoprostol-alone group. Data from 105 women in mifepristone group and 103 women in misoprostol-alone group were analyzed, with no differences in baseline characteristics. The median time between medications (oral mifepristone/placebo and vaginal misoprostol) was nearly 43 h in both groups (p = 0.906). The median time to first follow-up was 2.6 weeks (IQR 1.0) in mifepristone group and 2.4 weeks (IQR 1.0) in misoprostol-alone group (p = 0.855). The overall success rate of medical treatment was significantly higher in the mifepristone-group comparing to misoprostol-alone group (94.3% vs. 82.5%, RR 1.14, 95% CI, 1.03–1.26; p = 0.008). Accordingly, the rate of surgical treatment was significantly lower in the mifepristone-group (5.7% vs.14.6%, RR 0.39, 95% CI, 0.16–0.97; p = 0.034). The composite complication rate was similar and lower than 4% in both groups. No case of complicated pelvic infection, hemodynamic instability or inpatient supportive treatment was reported. There were no significant differences in the rates of adverse events, median score for vaginal bleeding intensity or analgesics use. Despite the same median value, the score of abdominal pain intensity was significantly higher in the mifepristone-group (p = 0.011). In both groups, more than 65% of the women classified the treatment as “good” and 92% would recommend it to a friend on the same clinical situation. ConclusionThe mifepristone plus vaginal misoprostol combined treatment for medical resolution of first trimester miscarriage resulted in significant higher success rate and lower rate of surgical uterine evacuation comparing to misoprostol-alone treatment, with no relevant differences in adverse events or treatment acceptability.

Glucocorticoid receptor modulator CORT125385 alleviates diet-induced hepatosteatosis in male and female mice

Non-alcoholic fatty liver disease (NAFLD) is a common condition that can progress to the more severe conditions like non-alcoholic steatohepatitis (NASH) for which limited effective therapeutic options are available. In this study, we set out to evaluate the novel glucocorticoid receptor modulator CORT125385, an analogue of the previously studied miricorilant but without mineralocorticoid receptor binding activity. Male and female mice that received high-fat diet and fructose water were treated with either vehicle, CORT125385 or mifepristone. We found that CORT125385 significantly lowered hepatic triglyceride levels in male mice, and hepatic triglyceride and cholesterol levels in female mice. Mifepristone treatment had no effect in male mice, but significantly lowered hepatic triglyceride and cholesterol levels in female mice. In reporter assays in vitro, CORT125385 showed weak partial agonism on the progesterone receptor (PR) at high doses, as well as PR antagonism at a potency 1000-fold lower than mifepristone. In vivo, CORT125385 treatment did not influence PR-responsive gene expression in the oviduct, while mifepristone treatment strongly influenced these genes in the oviduct, thus excluding in vivo PR cross-reactivity of CORT125385 at a therapeutically active dose. We conclude that CORT125385 is a promising glucocorticoid receptor modulator that effectively reduces liver steatosis in male and female mice without affecting other steroid receptors at doses that lower hepatic lipid content.

Effect of Mifepristone vs Placebo for Treatment of Adenomyosis With Pain Symptoms

Adenomyosis is a common chronic gynecological disorder, and its treatment is an unmet need. New therapies need to be developed. Mifepristone is being tested for adenomyosis treatment. To determine whether mifepristone is effective and safe for adenomyosis treatment. This multicenter, placebo-controlled, double-blind randomized clinical trial was conducted in 10 hospitals in China. In total, 134 patients with adenomyosis pain symptoms were enrolled. Trial enrollment began in May 2018 and was completed in April 2019, and analyses were conducted from October 2019 to February 2020. Participants were randomized 1:1 to receive mifepristone 10 mg or placebo orally once a day for 12 weeks. The primary end point was the change in adenomyosis-associated dysmenorrhea intensity, evaluated by the visual analog scale (VAS) after 12 weeks of treatment. Secondary end points included the change in menstrual blood loss, increased level of hemoglobin in patients with anemia, CA125 level, platelet count, and uterine volume after 12 weeks of treatment. Safety was assessed according to adverse events, vital signs, gynecological examinations, and laboratory evaluations. In total, 134 patients with adenomyosis and dysmenorrhea were randomly assigned, and 126 patients were included in the efficacy analysis, including 61 patients (mean [SD] age, 40.2 [4.6] years) randomized to receive mifepristone and 65 patients (mean [SD] age, 41.7 [5.0] years) randomized to received the placebo. The characteristics of the included patients at baseline were similar between groups. The mean (SD) change in VAS score was -6.63 (1.92) in the mifepristone group and -0.95 (1.75) in the placebo group (P < .001). The total remission rates for dysmenorrhea in the mifepristone group were significantly better than those in the placebo group (effective remission: 56 patients [91.8%] vs 15 patients [23.1%]; complete remission: 54 patients [88.5%] vs 4 patients [6.2%]). All the secondary end points showed significant improvements after mifepristone treatment for menstrual blood loss, hemoglobin (mean [SD] change from baseline: 2.13 [1.38] g/dL vs 0.48 [0.97] g/dL; P < .001), CA125 (mean [SD] change from baseline: -62.23 [76.99] U/mL vs 26.89 [118.70] U/mL; P < .001), platelet count (mean [SD] change from baseline: -28.87 [54.30]×103/µL vs 2.06 [41.78]×103/µL; P < .001), and uterine volume (mean [SD] change from baseline: -29.32 [39.34] cm3 vs 18.39 [66.46] cm3; P < .001). Safety analysis revealed no significant difference between groups, and no serious adverse events were reported. This randomized clinical trial showed that mifepristone could be a new option for treating patients with adenomyosis, based on its efficacy and acceptable tolerability. ClinicalTrials.gov Identifier: NCT03520439.

Abstract 3994: Differential regulation of hormone receptors and Ki67 in luminal breast carcinomas and tumor-adjacent mammary glands by mifepristone treatment

Abstract Since antiprogestins inhibit the growth of preclinical mammary tumor models expressing higher levels of progesterone receptor (PR) isoform A (PRA) than isoform B (PRB), we designed a window-of-opportunity trial (MIPRA; NCT02651844) to study the benefits of mifepristone (MFP) in luminal breast carcinomas from postmenopausal patients selected by their PR+ expression (&amp;gt;50%) and their PR isoform ratio (PRA/PRB&amp;gt;1.5; PRA-H). A decrease in the cell proliferation marker Ki67 was registered after treatment in 14 out of the 20 tumors evaluated. This inhibition was associated with a decrease in PR, estrogen receptor (ER) and pSer118ER evaluated by immunohistochemistry while no changes in pSer167ER expression were observed (PMID: 36269797). In selected tissues from these samples we observed that the staining intensity in trapped glands within the MFP-treated tumors did not follow a similar trend as that of tumor cells. Thus, the aim of this study was to evaluate the expression of hormone receptors and Ki67 in non-neoplastic human mammary glands (nnMG) adjacent to the PRA-H tumor tissue of postmenopausal patients, treated (n=8) or not (n=9) with MFP. No differences in PR, ER and pSer118ER expression were observed between MFP-treated nnMG and those from untreated patients. Notably, contrarily to what occurred in tumors, there was a significant decrease of pSer167ER expression (p=0.008) in the MFP-treated nnMG compared to the untreated glands, suggesting a selective modulation in the AKT-mediated activation of ER. Regarding the proliferative state of the nnMGs, there was a slight but significant increase (p=0.02) in Ki67 expression in MFP-treated vs. non-treated nnMG. Data regarding the effect of antiprogestins in normal mammary glands is limited and points, in premenopausal women, to a decrease in the Ki67 index after treatment. The basal quiescent status of nnMG in postmenopausal women may explain this slight stimulatory effect. In conclusion, our results show that MFP exerts a specific regulatory effect in PRA-H tumors that is not observed in the nnMG, probably due to the fact that nnMG have presumably equimolar levels of PRA and PRB. In addition, to counteract the possible stimulatory effect that MFP may induce on nnMG, the combination of MFP and tamoxifen treatment is suggested. Citation Format: Leo Saldain, Silvia Vanzulli, Paula Martinez Vazquez, Javier Burruchaga, Eunice Spengler, Claudia Lanari, Paola Rojas. Differential regulation of hormone receptors and Ki67 in luminal breast carcinomas and tumor-adjacent mammary glands by mifepristone treatment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3994.

Abstract 3082: Altered levels of corticosteroid-binding globulin: SerpinA6 and progression of prostate cancer

Abstract SerpinA6 is a main transport protein for cortisol binding, which helps in cortisol tissue delivery particularly at inflammatory sites. Cortisol plays a vital role in adaptation to stress, modulating fuel metabolism, and inflammation. SerpinA6 releases cortisol specifically at inflammatory sites upon cleavage by human neutrophil elastase between residues 344 and 345. Castration induce inflammation in the prostate increases glucocorticoids (GCs) level and elevates pro-inflammatory cytokine IL-6 levels. European and Asian populations represented association between single nucleotide polymorphisms (SNPs) in CYP17A1 and SERPINA6/A1 and circulating glucocorticoid concentrations. We propose increasing IL-6 levels after castration alters SerpinA6 levels in prostate may results in prostate cancer disease progression. Deficient SerpinA6 may not be sufficient to keep steroids inactive, due to the increasing GCs. Our data suggests IL-6 treatment of androgen independent prostate cancer (PC-3) cells decreases SerpinA6 level and conversely increases glucocorticoid receptor (GR) expression in a dose (1-10ng/ml) and time (30-180 minutes) dependent fashion. Moreover, IL-6 dose dependent treatment in PC-3 cells decreases FOXO3a expression, a major apoptotic protein dysregulated in prostate cancer. Next, we determine the role of SerpinA6 (30µg/ml) and IL-6 (5ng/ml) independently and in combination to PC-3 cells. We observed IL-6 and SerpinA6 co-treatment to PC-3 cells (charcoal stripped FBS media) for 6 hours reduced Neutrophil elastase levels significantly. Silencing IL-6 in PC-3 cells increased SerpinA6 expression. Moreover, silencing SerpinA6 in metastatic variant of PC-3 cells increased phospho-Akt-(ser-473), glucocorticoid receptor and increased apoptotic protein FOXO3a expressions. Using dexamethasone (15µM), which is known to suppress PC-3 cell migration, we found increased expression of SerpinA6. Conversely, Mifepristone (15µM), which inhibits PC-3 cell growth, deceases SerpinA6 expression after 24 hours of treatment. In humans the normal range of circulatory SerpinA6 level are 19-45µg/ml. We treated normal prostate epithelial cells (RWPE1) and prostate cancer (PC-3) cells with human recombinant protein 18 and 36µg/ml of doses for 24 hours; RWPE1 cells represented a SerpinA6 dose dependent increase in cellular viability, whereas PC-3 cells demonstrated no change in the viability after a dose response treatment with SerpinA6 for 24 hours. In-vivo data represented altered SerpinA6 levels in castrated TRansgenic Adenocarcinoma Mouse Prostate model after dexamethasone (GR agonist) and Mifepristone (GR antagonist) treatment. We suggest decreasing levels of SerpinA6 in prostate cancer patients may have potential role in disease progression. We need to have an effective agent, to prevent maintain SerpinA6 level to inhibit the progression of prostate cancer. Citation Format: Mohammed Al-Toubat, Jatinder Kumar, Shiva Gautam, Kethandapatti Balaji, Sanjeev Shukla. Altered levels of corticosteroid-binding globulin: SerpinA6 and progression of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3082.

Direct Effects of Mifepristone on Mice Embryogenesis: An In Vitro Evaluation by Single-Embryo RNA Sequencing Analysis

The clinical use of mifepristone for medical abortions has been established in 1987 in France and since 2000 in the United States. Mifepristone has a limited medical period that lasts <9 weeks of gestation, and the incidence of mifepristone treatment failure increases with gestation time. Mifepristone functions as an antagonist for progesterone and glucocorticoid receptors. Studies have confirmed that mifepristone treatments can directly contribute to endometrium disability by interfering with the endometrial receptivity of the embryo, thus causing decidual endometrial degeneration. However, whether mifepristone efficacy directly affects embryo survival and growth is still an open question. Some women choose to continue their pregnancy after mifepristone treatment fails, and some women express regret and seek medically unapproved mifepristone antagonization with high doses of progesterone. These unapproved treatments raise the potential risk of embryonic fatality and developmental anomalies. Accordingly, in the present study, we collected mouse blastocysts ex vivo and treated implanted blastocysts with mifepristone for 24 h. The embryos were further cultured to day 8 in vitro to finish their growth in the early somite stage, and the embryos were then collected for RNA sequencing (control n = 3, mifepristone n = 3). When we performed a gene set enrichment analysis, our data indicated that mifepristone treatment considerably altered the cellular pathways of embryos in terms of viability, proliferation, and development. The data indicated that mifepristone was involved in hallmark gene sets of protein secretion, mTORC1, fatty acid metabolism, IL-2-STAT5 signaling, adipogenesis, peroxisome, glycolysis, E2F targets, and heme metabolism. The data further revealed that mifepristone interfered with normal embryonic development. In sum, our data suggest that continuing a pregnancy after mifepristone treatment fails is inappropriate and infeasible. The results of our study reveal a high risk of fetus fatality and developmental problems when pregnancies are continued after mifepristone treatment fails.

Mifepristone-misoprostol combination treatment for early pregnancy loss after embryo transfer: a case series

Evidence strongly supports the use of mifepristone-misoprostol combination treatment for early pregnancy loss (EPL) among pregnancies conceived without assisted reproductive technologies. No literature exists, however, regarding the efficacy of this treatment in the medical management of EPL among pregnancies after invitro fertilization and embryo transfer (IVF-ET). These patients differ as some use exogenous hormonal supplementation to provide pregnancy support. Thus, the management for EPL may differ between unassisted conceptions and those after ET. Mifepristone, a progesterone receptor antagonist, may demonstrate an altered treatment effect when used with misoprostol to manage EPL in assisted reproductive technologie-conceived pregnancies. To describe our institution's experience using mifepristone-misoprostol to manage EPL after invitro fertilization with embryo transfer IVF-ET. Retrospective case series. Single academic institution from 2020 to2022. Nine patients with ultrasound confirmed EPL after IVF-ET. All 9 patients underwent invitro fertilization followed by fresh or frozen embryo transfer. All 9 received 200 mg of mifepristone 24 hours before 800 μg of misoprostol. Incomplete abortion, need for surgical management, number of days to negative serum human chorionic gonadotropin (hCG). Of the 9 subjects included, one had a programmed frozen embryo transfer cycle, 6 had modified natural frozen embryo transfer cycles, and 2 underwent fresh ET. Eight subjects had successful expulsion of tissue with one dose of treatment, and one required uterine aspiration. No subjects required additional dosing of misoprostol. The mean number of days elapsed from mifepristone treatment to tissue expulsion was 4.89 ± 11.30 days and the mean days to negative-range serum hCG was 36.89 ± 18.59 days. At the initial ultrasound, all pregnancies had one gestational sac seen; 5/9 had a yolk sac; only 3 had fetal cardiac activity. The mean gestational age at the time of EPL diagnosis was 55.22 ± 8.77 days, with the majority (8/9) having completed 7 weeks gestation. Mifepristone-misoprostol combination treatment appears to be a reasonable option for those with EPL after IVF-ET. Future, larger-scale studies are needed comparing combination treatment with misoprostol only among various ET protocols.

Mifepristone increases AQP1 mRNA expression, angiogenesis, and cell permeability through the ERK MAPK pathway.

The purpose of this study was to investigate the mechanism of mifepristone serves as an anti-implantation contraceptive drug on aquaporins 1 (AQP1) expression. Human umbilical vein endothelial cells (HUVECs) were used to detect the effects of different concentrations of mifepristone (0, 0.065, 0.2, and 1μmol/L) on the activity of angiogenesis and AQP1 expression. The expression of AQP1 was tested by the real-time PCR. The angiogenesis and penetration function of HUVECs was investigated by Matrigel lumen formation and trans-well assay, respectively. The expression of AQP1, angiogenesis and cell permeability were significantly higher than control groups in HUVECs treatment with mifepristone at 1μmol/L for 12h. Estrogen and progesterone decreased the up-regulation of AQP1 and cell permeability, not angiogenesis, induced by mifepristone. Mifepristone increased protein levels of p-ERK, not p-p38 or p-JNK, and pre-treatment with ERK MAPK-specific inhibitor significantly inhibited the up-regulation of AQP1 mRNA expression, angiogenesis and cell permeability induced by mifepristone. si-AQP1 significantly reduced the up-regulation of angiogenesis, cell permeability and p-ERK/ERK ratio expression induced by mifepristone treatment. Overexpression of AQP1 enhanced the increase of expression ratio of p-ERK/ERK induced by mifepristone. Low-dose mifepristone increased cell permeability, angiogenesis and AQP1 expression, which was involved in MAPK pathways. This provides new insights into the molecular mechanism of mifepristone serves as an anti-implantation contraceptive drug.

Two cases of infantile-onset primary generalized glucocorticoid hypersensitivity and the effect of mifepristone

BackgroundPrimary generalized glucocorticoid hypersensitivity (PGGH) is a very rare disease caused by terminal organ hypersensitivity to glucocorticoids for which the aetiology is unknown. The incidence of PGGH is extremely rare, especially in children. To date, the literatures about the etiology, prognosis and treatment of PGGH are scarce. Aim of the study is describing the cases of two Chinese children with infantile-onset PGGH in one family, one of whom died and one who was treated with mifepristone. They are the two youngest children with PGGH reported in the literature.Case presentationTwo siblings with infantile-onset PGGH were affected in this family. The main manifestations of patient 1 were typical Cushing’s syndrome-like manifestations, significantly aggravated symptoms after physiological doses of glucocorticoids and very low levels of serum cortisol and adrenocorticotropin hormone (ACTH) during attacks. After being diagnosed with PGGH, he was given guidance to avoid glucocorticoids and took mifepristone therapy for 5 months, and his symptoms improved. Patient 2 was the younger brother of patient 1, with similar manifestations to his brother at the age of 4 months. Patient 2 ultimately died at the age of 9 months.ConclusionPGGH is a very rare disease that can lead to death if not diagnosed and treated in a timely manner. This article describes the cases of the two youngest children with PGGH reported in the literature, one of whom improved after mifepristone treatment, and increases the knowledge of the clinical manifestations of and the treatment experience in PGGH.

ODP322 Impact of Mifepristone on Liver Function and Resolution of Liver Steatosis in Patients with Cushing Syndrome – A Case Study

Abstract Background Hypercortisolism is a recognized cause of non-alcoholic fatty liver disease (NAFLD). Mifepristone (Korlym®, Corcept Therapeutics), a glucocorticoid receptor (GR) antagonist, is FDA-approved for the treatment of hyperglycemia in patients with endogenous Cushing syndrome (CS). Mifepristone has also shown beneficial effects in preclinical models of fatty liver disease, including reduced liver injury, improved insulin sensitivity, and increased plasma adiponectin concentrations. Here, we report the case of a patient with CS and liver steatosis who was treated intermittently with mifepristone. Clinical Case A 36-year-old woman with CS associated with uncontrolled type 2 diabetes mellitus, obesity, major depressive disorder, hyperlipidemia, hypertension, and liver steatosis was intermittently treated with mifepristone for 3 years. Abdominal imaging was performed several times for abdominal pain. Before treatment with mifepristone was initiated, the patient had a body weight of 198 lbs, BMI of 32kg/m 2, HbA1c of 11.5%, and liver steatosis as noted on abdominal imaging with normal liver function tests (ALT: 40 U/L [normal: 6-42 U/L], AST: 30 U/L [normal: 8-36 U/L]). After 16 months, treatment with mifepristone was discontinued secondary to abnormal uterine bleeding. Imaging performed around the time of discontinuation showed resolution of liver steatosis, which was accompanied by significant reductions in LFTs to levels typically seen in healthy volunteers without liver steatosis (ALT: 10 U/L, AST: 17 U/L). The patient's HbA1c had decreased to 6.8%. Imaging performed 7months after mifepristone discontinuation showed recurrence of liver steatosis, LFTs had returned to pre-treatment values (ALT: 42 U/L, AST: 31U/L), and HbA1c had increased to 9.3%. The patient underwent hysterectomy and restarted mifepristone treatment. One year after resumption of mifepristone, imaging showed that liver steatosis had resolved once again, along with a similar reduction in LFTs as observed before (ALT: 16 U/L, AST: 12 U/L). Fourteen months after restart, mifepristone was discontinued again. Labs and imaging performed 10 months after discontinuation showed, as previously, recurrence of liver steatosis along with elevated LFTs (ALT: 100 U/L, AST: 56 U/L). Data from mifepristone's prospective pivotal study (SEISMIC, NCT00569582) of 50 patients with CS also showed a similar reduction in ALT throughout the study, which was reversed during the 6-week discontinuation follow-up phase of the study. This was followed by a repeat reduction when mifepristone was restarted in the extension study (NCT00936741). Conclusion These results suggest that mifepristone is effective in improving liver function and decreasing liver steatosis in patients with endogenous CS, a trend that is also accompanied by improvement in insulin resistance and glycemic control. Presentation: No date and time listed

The effects of mifepristone on the structure of human decidua and chorion and Bax and Bcl-2 expression at early stage of pregnancy

BackgroundAs a progesterone receptor antagonist, mifepristone combined with misoprostol is widely used to terminate early pregnancy in clinical practice. It has also been reported that mifepristone may cause cell death in decidual cells and result in hemorrhage of the decidua and insufficient blood supply. However, little is known about the histological effects of mifepristone on human decidua and chorion.MethodsHistological and subcellular structural changes of decidua and chorionic villi from women taking mifepristone at early pregnancy times were examined by Hematoxylin and eosin (H&E) staining and transmission Electron microscope. The expression of apoptosis-related proteins Bax/Bcl-2 was examined by immunohistochemistry.ResultsAfter 48 h of mifepristone administration, the decidua tissue and chorionic villus structures were altered in women within 39–49 days of gestation and displayed varying degrees of degeneration and necrosis-like features. Apoptotic events were observed in the decidua and chorionic villi of early pregnancy, and mifepristone treatment significantly increases the number of apoptotic cells. The increased apoptotic events were concomitant with the increased expression of Bax and decreased expression of Bcl-2.ConclusionThis study provides evidence that mifepristone induces histological and subcellular changes in decidua and chorionic villi. Mifepristone modulates the relative ratio of Bax/Bcl-2 and the increased apoptosis contributes to the pregnancy termination at early stage of pregnancy.

Yikang decoction facilitates embryo implantation in mice with implantation dysfunction via upregulation of LIF expression

ObjectiveThe present study investigates the effects and mechanisms of Yikang decoction on embryo implantation in mice. MethodsTotally, mature female mice were randomly divided into four groups: normal, implantation failure (mifepristone treatment), Yikang decoction treatment (mifepristone and Yikang decoction treatment), and control (mifepristone and physiological saline treatment) groups. The efficacy of Yikang decoction was evaluated by the adhesion of uterine endometrial cells. The expression of leukemia inhibitory factor (LIF) and integrin αvβ3 in the endometrium were detected by real-time quantitative PCR and western blot. In addition, mouse endometrial cells were transfected with LIF specific siRNA-1, and the expression of LIF and αvβ3 were detected. ResultsThe number of embryos markedly decreased after mifepristone treatment. The adhesion of endometrial cells in the Yikang decoction treatment group significantly increased, when compared to the control group. The expression of LIF and integrin αvβ3 was significantly reduced by mifepristone, but the attenuated expression of LIF and αvβ3 was markedly reversed by treatment with Yikang decoction. In addition, after LIF siRNA-1 transfection, the expression of integrin αvβ3 significantly decreased (P < 0.01). The correlation analysis revealed a significant positive correlation between LIF and αvβ3 protein expression. ConclusionYikang decoction can regulate the expression of αvβ3 and increase cell adhesion by upregulating the expression of LIF, thereby improving embryo implantation in mice. These data suggest that Yikang decoction may have therapeutic effect in treating infertility.