Effect Of Mifepristone Research Articles

Effects of mifepristone, a model compound with anti-progestogenic activity, on the reproduction of African clawed frog (Xenopus laevis)

This is the first study on how a substance with anti-progestogenic activity affects amphibian reproduction. Mifepristone, a synthetic anti-progestin used in abortion pills, was chosen as model compound. African clawed frog (Xenopus laevis) females were exposed to four mifepristone concentrations (0.7, 9, 120, and 1380ng∙L−1) for 30 days. A control group was also included. Egg-laying during the experiment was significantly less at the highest concentration. At the experiment’s end, mifepristone-exposed and control females were randomly mated with sexually mature males. Breeding rate for females exposed to 1380ng∙L−1 mifepristone was only 50%. Histology revealed no significant changes in gonads, thyroid, or liver. Females exposed to 1380ng∙L−1 mifepristone had lower estradiol levels in plasma, lower mRNA expression of lh and fsh in brain–pituitary complex, and p450scc in ovaries. In liver, mRNA level of npr was significantly increased in females exposed to 120ng∙L−1 mifepristone. mRNA expression of mpr, erβ, dio2, and dio3 were upregulated in animals exposed to 9ng∙L−1 and 120ng∙L−1 mifepristone, whereas vtg expression was significantly downregulated in females exposed to 1380ng∙L−1 mifepristone. All these findings show that exposure to compounds with anti-progestogenic activity affects the hypothalamus–pituitary–gonad axis and decreases reproductive success.

Targeting delivery of mifepristone to endometrial dysfunctional macrophages for endometriosis therapy

Endometriosis seriously affects 6–10 % of reproductive women globally and poses significant clinical challenges. The process of ectopic endometrial cell colonization shares similarities with cancer, and a dysfunctional immune microenvironment, characterized by non-classically polarized macrophages, plays a critical role in the progression of endometriosis. In this study, a targeted nano delivery system (BSA@Mif NPs) was developed using bovine serum albumin (BSA) as the carrier of mifepristone. The BSA@Mif NPs were utilized to selectively target M2 macrophages highly enriched in ectopic endometrial tissue via the SPARC receptor. This targeting strategy increases drug concentration at ectopic lesions while minimizing its distribution to normal tissue, thereby reducing side effects. In vitro studies demonstrated that BSA@Mif NPs not only enhanced the cellular uptake of M2-type macrophages and ectopic endometrial cells but also improved the cytotoxic effect of mifepristone on ectopic endometrial cells. Furthermore, the BSA@Mif NPs effectively induced immunogenic cell death (ICD) in ectopic endometrial cells and repolarized M2-type macrophages toward the M1 phenotype, resulting in a synergistic inhibition of ectopic endometrial cell growth. In vivo experiments revealed that BSA@Mif NPs exhibited significant therapeutic efficacy in endometriosis-bearing mice by increasing drug accumulation in the endometriotic tissues and modulating the immune microenvironment. This targeted biomimetic delivery strategy presents a promising approach for the development of endometriosis-specific therapies based on existing drugs. Statement of significanceMacrophages play an essential role in immune dysfunctional microenvironment promoting the occurrence and progression of endometriosis and can be a crucial target for developing immune microenvironment regulation strategies for the unmet long-term management of endometriosis. The albumin nanoparticles constructed based on SPARC overexpression in macrophages and endometrial cells and albumin biosafety can achieve the targeted therapy of endometriosis by increasing the passive- and active-mediated drug accumulation in ectopic endometrium and remodeling the immune microenvironment based on macrophage regulation. This study has the following implications: i) overcoming the inherent shortcomings of clinical drugs by nanotechnology is an alternative way of developing medication; ii) developing microenvironment modulation strategies based on macrophage regulation for endometriosis management is feasible.

Effect of Mifepristone on Migration and Proliferation of Oral Cancer Cells.

Glucocorticoid receptor (GR) overexpression has been linked to increased tumour aggressiveness and treatment resistance. GR antagonists have been shown to enhance treatment effectiveness. Emerging research has investigated mifepristone, a GR antagonist, as an anticancer agent with limited research in the context of oral cancer. This study investigated the effect of mifepristone at micromolar (µM) concentrations of 1, 5, 10 and 20 on the proliferation and migration of oral cancer cells, at 24 and 48 h. Scratch and scatter assays were utilised to assess cell migration, MTT assays were used to measure cell proliferation, Western blotting was used to investigate the expression of GR and the activation of underlying Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) signalling pathways, and immunofluorescence (IF) was used to determine the localisation of proteins in HaCaT (immortalised human skin keratinocytes), TYS (oral adeno squamous cell carcinoma), and SAS-H1 cells (squamous cell carcinoma of human tongue). Mifepristone resulted in a dose-dependent reduction in the proliferation of HaCaT, TYS, and SAS-H1 cells. Mifepristone at a concentration of 20 µM effectively reduced collective migration and scattering of oral cancer cells, consistent with the suppression of the PI3K-Akt and MAPK signalling pathways, and reduced expression of N-Cadherin. An elongated cell morphology was, however, observed, which may be linked to the localisation pattern of E-Cadherin in response to mifepristone. Overall, this study found that a high concentration of mifepristone was effective in the suppression of migration and proliferation of oral cancer cells via the inhibition of PI3K-Akt and MAPK signalling pathways. Further investigation is needed to define its impact on epithelial-mesenchymal transition (EMT) markers.

Ketogenic Diet Enhances the Anti-Tumor Effect of Mifepristone in a Breast Cancer Mouse Model

Ketogenic Diet Enhances the Anti-Tumor Effect of Mifepristone in a Breast Cancer Mouse Model

Conditional Inhibition of Eip75B Eliminates the Effects of Mating and Mifepristone on Lifespan in Female Drosophila.

Mating in female Drosophila melanogaster causes midgut hypertrophy and reduced lifespan, and these effects are blocked by the drug mifepristone. Eip75B is a transcription factor previously reported to have pleiotropic effects on Drosophila lifespan. Because Eip75B null mutations are lethal, conditional systems and/or partial knock-down are needed to study Eip75B effects in adults. Previous studies showed that Eip75B is required for adult midgut cell proliferation in response to mating. To test the possible role of Eip75B in mediating the lifespan effects of mating and mifepristone, a tripartite FLP-recombinase-based conditional system was employed that provides controls for genetic background. Expression of a Hsp70-FLP transgene was induced in third instar larvae by a brief heat pulse. The FLP recombinase catalyzed the recombination and activation of an Actin5C-GAL4 transgene. The GAL4 transcription factor in turn activated expression of a UAS-Eip75B-RNAi transgene. Inhibition of Eip75B activity was confirmed by loss of midgut hypertrophy upon mating, and the lifespan effects of both mating and mifepristone were eliminated. In addition, the negative effects of mifepristone on egg production were eliminated. The data indicate that Eip75B mediates the effects of mating and mifepristone on female midgut hypertrophy, egg production, and lifespan.

Effects of mifepristone on adipocyte differentiation in mouse 3T3-L1 cells

BackgroundBoth glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ) play a critical role in adipocyte differentiation. Mifepristone is not only an antagonist of the glucocorticoid receptor but also an agonist of PPARγ. Therefore, the present study investigated the effect of mifepristone on adipocyte differentiation.MethodsMouse 3T3-L1 cells were used as a model for adipocyte differentiation. The lipid droplet formation was evaluated with Bodipy493/503 staining and the expression of adipocyte markers [adiponectin and adipocyte fatty acid binding protein-4 (Fabp4)] was evaluated with quantitative PCR and immunoblot analyses for indication of adipocyte differentiation. siRNA and neutralizing antibodies were used to elucidate the molecular mechanism of mifepristone-induced adipocyte differentiation. Luciferase reporter assay was used to examine the effect of mifepristone on the promoter activity of PPAR-response element (PPRE). The DNA microarray analysis was used to characterize the transcriptome of the mifepristone-induced adipocytes. In vivo adipogenic effect of mifepristone was examined in mice.ResultsMifepristone not only enhanced adipocyte differentiation induced by the conventional protocol consisting of insulin, dexamethasone and 3-isobutyl-1-methylxanthine but also induced adipocyte differentiation alone, as evidenced by lipid droplets formation and induction of the expression of adiponectin and Fabp4. These effects were inhibited by an adiponectin-neutralizing antibody and a PPARγ antagonist. Mifepristone activated the promoter activity of PPRE in a manner sensitive to PPARγ antagonist. A principal component analysis (PCA) of DNA microarray data revealed that the mifepristone-induced adipocytes represent some characteristics of the in situ adipocytes in normal adipose tissues to a greater extent than those induced by the conventional protocol. Mifepristone administration induced an increase in the weight of epididymal, perirenal and gluteofemoral adipose tissues.ConclusionsMifepristone alone is capable of inducing adipocyte differentiation in 3T3-L1 cells and adipogenesis in vivo. PPARγ plays a critical role in the mifepristone-induced adipocyte differentiation. Mifepristone-induced adipocytes are closer to the in situ adipocytes than those induced by the conventional protocol. The present study proposes a single treatment with mifepristone as a novel protocol to induce more physiologically relevant adipocytes in 3T3-L1 cells than the conventional protocol.

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.

Mifepristone decreases nicotine intake in dependent and non-dependent adult rats.

Addiction to tobacco and nicotine products has adverse health effects and afflicts more than a billion people worldwide. Therefore, there is an urgent need for new treatments to reduce tobacco and nicotine use. Glucocorticoid receptor blockade shows promise as a novel treatment for drug abuse and stress-related disorders. These studies aim to investigate whether glucocorticoid receptor blockade with mifepristone diminishes the reinforcing properties of nicotine in rats with intermittent or daily long access to nicotine. The rats self-administered 0.06 mg/kg/inf of nicotine for 6 h per day, with either intermittent or daily access for 4 weeks before treatment with mifepristone. Daily nicotine self-administration models regular smoking, while intermittent nicotine self-administration models occasional smoking. To determine whether the rats were dependent, they were treated with the nicotinic acetylcholine receptor antagonist mecamylamine, and somatic signs were recorded. The rats with intermittent access to nicotine had a higher level of nicotine intake per session than those with daily access but only the rats with daily access to nicotine showed signs of physical dependence. Furthermore, mecamylamine increased nicotine intake during the first hour of access in rats with daily access but not in those with intermittent access. Mifepristone decreased total nicotine intake in rats with intermittent and daily access to nicotine. Moreover, mifepristone decreased the distance traveled and rearing in the open field test and operant responding for food pellets. These findings indicate that mifepristone decreases nicotine intake but this effect may be partially attributed to the sedative effects of mifepristone.

Pharmacist dispensing of mifepristone: An opinion of the Women's Health Practice and Research Network of the American College of Clinical Pharmacy

AbstractA rising percentage of patients are electing medication abortion over procedural abortion for increased safety and privacy. Access to medication abortion is essential healthcare, but many Americans face unsurmountable barriers when pursuing this option. This has been in large part due to unnecessary restrictions imposed by the United States Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) for mifepristone, used in combination with misoprostol for medication abortion. Moreover, many states have imposed additional restrictions on abortion, further impeding access to care. Since its original approval in 2000, mifepristone can only be prescribed by certified prescribers. Until recently, mifepristone could only be dispensed by certified prescribers, whereby more accessible community and mail‐order pharmacies were prohibited from dispensing mifepristone. During the Coronavirus disease 2019 public health emergency, there was a temporary allowance for certified prescribers to utilize mail or mail‐order pharmacies to deliver medications to patients. In January 2023, the FDA approved modifications to the mifepristone REMS to allow certified pharmacies to dispense the medication. Given the established safety and effectiveness of mifepristone, the evidence supports its distribution via pharmacies and leveraging pharmacists to expand medication abortion access. Pharmacists are one of the most widely accessible healthcare providers and their responsibility centers on patient and medication safety and improving health outcomes. This article, an opinion of the American College of Clinical Pharmacy Women's Health Practice and Research Network, adds the voice of members of the pharmacy profession to the collective efforts to ensure access to medication abortion, including pharmacist dispensing of mifepristone. We encourage pharmacists to embrace this fresh opportunity to provide medication abortion care in their communities.

Dhr96[1] mutation and maternal tudor[1] mutation increase life span and reduce the beneficial effects of mifepristone in mated female Drosophila.

Mating and receipt of male Sex Peptide hormone cause increased egg laying, increased midgut size and decreased life span in female Drosophila. Feeding mated females with the synthetic steroid mifepristone decreases egg production, reduces midgut size, and increases life span. Here, several gene mutations were assayed to investigate possible mechanisms for mifepristone action. Drosophila Dhr96 is a hormone receptor, and a key positive regulator of midgut lipid uptake and metabolism. Dhr96[1] null mutation increased female life span, and reduced the effects of mifepristone on life span, suggesting that Dhr96[1] mutation and mifepristone may act in part through the same mechanism. Consistent with this idea, lipidomics analysis revealed that mating increases whole-body levels of triglycerides and fatty-acids in triglycerides, and these changes are reversed by mifepristone. Maternal tudor[1] mutation results in females that lack the germ-line and produce no eggs. Maternal tudor[1] mutation increased mated female life span, and reduced but did not eliminate the effects of mating and mifepristone on life span. This indicates that decreased egg production may be related to the life span benefits of mifepristone, but is not essential. Mifepristone increases life span in w[1118] mutant mated females, but did not increase life span in w[1118] mutant virgin females. Mifepristone decreased egg production in w[1118] mutant virgin females, indicating that decreased egg production is not sufficient for mifepristone to increase life span. Mifepristone increases life span in virgin females of some, but not all, white[+] and mini-white[+] strains. Backcrossing of mini-white[+] transgenes into the w[1118] background was not sufficient to confer a life span response to mifepristone in virgin females. Taken together, the data support the hypothesis that mechanisms for mifepristone life span increase involve reduced lipid uptake and/or metabolism, and suggest that mifepristone may increase life span in mated females and virgin females through partly different mechanisms.

Mifepristone Modulates the Polarization of Th1/Th2 by Inducing the Mature of Monocyte‐Derived Dendritic Cells

AbstractAs an anti‐implantation contraception medicine, mifepristone can alter the development of the endometrium. In contrast, little research is performed to decipher the effect of mifepristone on Th1/Th2 immune homeostasis in the endometrium. CD14+ monocytes derived from healthy donors are cultured with interleukin (IL)‐4 and granulocyte macrophage‐colony stimulating factor to induce monocyte‐derived dendritic cells (DCs), which are further incubated with mifepristone. Mifepristone incubation could induce up‐regulated CD83 and major histocompatibility complex cell surface receptor staining on monocyte‐derived DCs. Functionally, mifepristone incubation could enhance the allostimulatory capacity of DCs to promote the proliferation of allogeneic T cells with up‐regulated Th1 cell proportion and down‐regulated Th2 cell proportion. On the other side, increased Th1 cytokines release (interferon‐γ, tumor necrosis factor α), inhibited Th2 cytokines release (IL‐10, IL‐4), promoted T‐Box transcription factor 21 transcription, and inhibited GATA binding protein 3 transcription are also identified. Mifepristone‐stimulated DCs could alter the Th1/Th2 transcription balance to favor Th1 skewing inflammatory environment.

Reversal of medication abortion with progesterone: a systematic review

BackgroundWe sought to determine whether there is evidence to recommend progesterone for individuals not wishing to complete a medication abortion after taking mifepristone.MethodsWe undertook an updated systematic review including a...

THU020 Bilateral Adrenal Hyperplasia (BAH): Undesirable Effect Of Glucocorticoid Receptor Competitive Antagonist (GRCAnt) In Cushing’s Disease

Abstract Disclosure: A. Canturk: None. C. Villabona: None. A. Kargi: None. We present a case of a complicated ACTH (adrenocorticotropic hormone)-dependent tumor and hypercortisolism, we discuss the potential side effects of mifepristone, a GRCAnt potentially causing bilateral adrenal hyperplasia and we discuss potential pathophysiologic mechanisms. This is a 73 years old male who presents to the clinic for a follow-up of Cushing’s Disease (CD). He has a pmh of osteoporosis, hypopituitarism, and secondary DM in the setting of an aggressive and medication-resistant Corticotroph Pituitary Neuroendocrine Tumor (cPNET). He has undergone a total of four transsphenoidal surgeries since 2013 and two treatments with external beam radiations. He still has residual tissue invading his cavernous sinus, thus another surgery was not an option, so Gamma Knife (GK) therapy was given. In the past, he has received a trial of ketoconazole for a period of 2-3 years, temozolomide, and octreotide, and is currently on mifepristone for the past four years. He underwent Bilateral Adrenalectomy in 2016 and had a small adrenal residual. It is demonstrated in a PET scan from 2018 that he had BAH and confirmed in a recent CT abdomen on 12/2022. While on mifepristone his ACTH was 1173pg/mL (nl:10 and 60 pg/mL), and cortisol 92.7 mcg/dL (nl:5 to 25 mcg/dL). Cortisol urine was 1627.2 mcg/24hr (nl:4 to 40 mcg/24hr). For treatment of his cPNET, we discontinued mifepristone and started on ketoconazole, and referred him to surgery for a second adrenalectomy. We reordered IHC on pathology specimens obtained in 2019 for SSTRs 1-5 and might consider starting synthetic somatostatin analog. We illustrate the potential negative effect of the long-term use of mifepristone. This is a GRCAnt that increases ACTH levels (8-10 fold in some cases) and will potentially cause BAH. This is an aggressive cPNET with hypercortisolism, who has been on long-standing medical therapy with mifepristone. He has developed BAH which has been potentially caused or exacerbated by GRCAnt. Reviewing the literature, there is limited data on this topic. This effect appears not to occur in all patients with Cushing’s disease. We propose potential pathophysiologic mechanisms of the indirect or direct effect of mifepristone causing BAH and potential factors explaining why this phenomenon might only occur in selected patients, we also propose management of patients on long therapy with GRCAnts. Presentation: Thursday, June 15, 2023

THU621 Mifepristone In Exogenous Cushing's Syndrome

Abstract Disclosure: S. Priyadarshan: None. D.O. Blavo: None. Introduction: Cushing’s syndrome is characterized by elevated cortisol levels in the body and is associated with significant morbidity and mortality. It can be broadly divided into endogenous and exogenous Cushing’s depending on etiology. Endogenous (body-produced) Cushing’s is diagnosed using Late Night Salivary Cortisol(LNSC), Dexamethasone Suppression Test(DST), or 24-hr Urinary-Free Cortisol(UFC) and after ruling out exogenous glucocorticoid administration. Hyperglycemia and weight gain are two of the many manifestations of Cushing’s that have hitherto proven to be a challenge to treat. Mifepristone is a glucocorticoid receptor antagonist that was recently FDA-approved for treating endogenous Cushing’s syndrome following the breakthrough SEISMIC trial. Literature regarding the utility of Mifepristone in exogenous Cushing’s has been limited since its approval. This case aims to fill that void. Case: A 35-year-old female with past medical history of rheumatoid arthritis was referred to endocrinology for further evaluation due to complaints of weight gain, dorso-cervical fat pad, abdominal striae, bruising of her right breast, and hirsutism requiring her to shave twice a week. She had previously been on prednisone 10mg-20mg daily for 2-3years for rheumatoid arthritis and was later weaned off due to her developing bruising, perioral abscess and dorsocervical fat pad. She was hospitalized for pneumonia later that year and discharged with dexamethasone. Her baseline weight at the time had been around 380lbs and she had a rapid weight gain over the next few weeks with a peak of 467lbs, associated with facial swelling and shortness of breath. For this, a DST was done per her primary provider among other labs and showed a cortisol level of 0.5mcg/dL(n<2mcg/dL). At the endocrine clinic, she had an extensive workup done including renin, aldosterone, plasma metanephrines, LH/FSH levels which all returned within normal limits. A1c was elevated at 6.7%(n <5.7%) and she was started on Metformin 1000mg BID. She had a repeat DST which suppressed cortisol appropriately however her midnight salivary cortisol was elevated. She was diagnosed with exogenous Cushing’s syndrome and started treatment with Mifepristone at 300mg daily. Her only side effect was mild nausea that later resolved. In 4 months, she had already lost 50lbs since her initial visit and HbA1c was down to 5.8. The dose was subsequently increased in increments up to 1200mg. In 7 months since starting Mifepristone, her weight was down to 312lbs, a total of 164lbs down from her initial weight. Her HbA1C was 4.6, down from her initial value of 6.7. Conclusion: This case is an excellent example of the effectiveness of Mifepristone in achieving glycemic control and weight reduction in Cushing’s syndrome with minimal side effects. More specifically, it serves to illustrate its utility in exogenous Cushing’s syndrome. Presentation: Thursday, June 15, 2023

Acute effects of mifepristone on emotional processing related brain activity: A functional MRI study

The Hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the pathophysiology of mood disorders, and preliminary data suggests that glucocorticoid receptor (GR) antagonism may be an important therapeutic mechanism. The effects of modulating HPA axis function on emotional processing related brain activity, which may be abnormal in depressed mood, is poorly understood. This study used a pharmacological functional magnetic resonance imaging (fMRI) design to determine the effects of the GR and progesterone receptor antagonist mifepristone on emotional faces processing task related brain activations in 19 right-handed healthy male participants. Each participant received 600 mg mifepristone or placebo on two separate imaging days and then performed an emotional processing fMRI task four hours later. The effect of mifepristone on task related brain activations was determined using Region-of-Interest (ROI) analyses and an exploratory whole brain voxel-wise analyses. No significant changes were observed in the defined ROIs (amygdala, anterior cingulate cortex, insula) or in the exploratory whole brain analyses that was associated with mifepristone administration in either the angry vs happy faces or angry and happy faces vs implicit baseline contrasts. Task reaction times and accuracy were similar in both mifepristone and placebo conditions (all p > 0.05). Our study failed to show significant evidence of modulation of emotional processing related brain activity associated with acute mifepristone administration. Future research should use fMRI to investigate the longer-term administration effects of mifepristone on mood in healthy participants and people with mood disorders to provide a deeper understanding of the potential effects on depressive symptoms.

The Role of Steroid Receptors in the Proliferation and Migration of Endometrial Adenocarcinoma HEC1A Cell Line

Objectives: Endometrial carcinoma is one of the most common gynecological cancers. It is generally divided into oestrogen-dependent type I, and oestrogen-independent type II. Although the expression of some steroid receptors has been documented in type II endometrial carcinoma, their roles in tumor progression have not been fully elucidated yet. Thus in this study, we aimed to examine the role of compounds acting on steroid receptors in type II, on HEC1A cultured cells.
 Methods: We tested the effect of mifepristone (the glucocorticoid and progesterone receptor blocker, 10-8M), bicalutamide (the androgen receptor blocker, 10-6M), G15 (the G-protein-coupled estrogen receptor-1 blocker, 10-7M) and PHTPP (2-Phenyl-3-(4-hydroxyphenyl)-5,7-bis (trifluoromethyl)-pyrazolo [1,5-a]pyrimidine, the estrogen receptor-β blocker, 10-7M), on proliferation. Proliferation was assessed by xCELLigence analysis system and migration was examined by using wound-healing model.
 Results: None of the drugs, at the used concentrations, have affected the proliferation of HEC1A cells. However, migration was significantly increased at the 24th and the 48th hour of mifepristone application (p

Effects of mifepristone, a model compound with anti-progestogenic activity, on the development of African clawed frog (Xenopus laevis)

The objective of this study was to assess the effects of a model substance with anti-progestogenic activity on development of African clawed frog (Xenopus laevis) from tadpole to juvenile stage. Mifepristone, a synthetic progesterone receptor-blocking steroid hormone used in medicine as an abortifacient, was chosen as a model compound with anti-progestogenic activity. In the experiment, African clawed frog tadpoles were exposed to mifepristone at three concentrations (2, 21, and 215 ng L−1). A control group was exposed to dimethyl sulfoxide (DMSO; 0.001 %). The experiment started when tadpoles reached stages 47–48 according to Nieuwkoop and Faber (NF; 1994) and continued until stage NF 66, when metamorphosis was complete. Exposure to mifepristone had no significant effect on the rate of tadpole development, occurrence of morphological anomalies, weight, body length, or sex ratio. Mortality was within an acceptable range of 0–3.6 % throughout the test and did not differ among the groups. Histopathological examination of the gonads and thyroid gland revealed no significant changes. Therefore, we can conclude that mifepristone had no negative effect on development of the African clawed frog up to juvenile stage. Nevertheless, at the highest tested mifepristone concentration (215 ng L−1), gene expression analysis revealed up-regulation of mRNA expression of nuclear progesterone receptor (npr), membrane progesterone receptor (mpr), estrogen receptor beta (esrβ), and luteinizing hormone (lh) in the brain–pituitary complex of exposed frogs at stage NF 66. Higher mRNA expression of npr was also found in frogs exposed to 22 ng L−1 mifepristone compared to the solvent control. These findings confirmed the anti-progestogenic activity of mifepristone in frogs because the up-regulation of progesterone receptors occurs if progesterone availability in the body is reduced. All the observed changes in combination may have negative consequences for reproduction and reproductive behavior later in life.

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.

Glucocorticoid receptors regulate central amygdala GABAergic synapses in Marchigian-Sardinian alcohol-preferring rats

Impairments in the function of the hypothalamic-pituitary-adrenal (HPA) axis and enhanced glucocorticoid receptor (GR) activity in the central amygdala (CeA) are critical mechanisms in the pathogenesis of alcohol use disorder (AUD). The GR antagonist mifepristone attenuates craving in AUD patients, alcohol consumption in AUD models, and decreases CeA γ-aminobutyric acid (GABA) transmission in alcohol-dependent rats. Previous studies suggest elevated GR activity in the CeA of male alcohol-preferring Marchigian-Sardinian (msP) rats, but its contribution to heightened CeA GABA transmission driving their characteristic post-dependent phenotype is largely unknown.We determined Nr3c1 (the gene encoding GR) gene transcription in the CeA in male and female msP and Wistar rats using in situ hybridization and studied acute effects of mifepristone (10 μM) and its interaction with ethanol (44 mM) on pharmacologically isolated spontaneous inhibitory postsynaptic currents (sIPSCs) and electrically evoked inhibitory postsynaptic potentials (eIPSPs) in the CeA using ex vivo slice electrophysiology.Female rats of both genotypes expressed more CeA GRs than males, suggesting a sexually dimorphic GR regulation of CeA activity. Mifepristone reduced sIPSC frequencies (GABA release) and eIPSP amplitudes in msP rats of both sexes, but not in their Wistar counterparts; however, it did not prevent acute ethanol-induced increase in CeA GABA transmission in male rats.In msP rats, GR regulates CeA GABAergic signaling under basal conditions, indicative of intrinsically active GR. Thus, enhanced GR function in the CeA represents a key mechanism contributing to maladaptive behaviors associated with AUD.

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.