Outcomes After Early Pregnancy Loss Management With Mifepristone Plus Misoprostol vs Misoprostol Alone.

Importance: Medication management of early pregnancy loss (EPL), or miscarriage, typically involves the administration of misoprostol with or without pretreatment with mifepristone. Combination treatment with mifepristone plus misoprostol is more effective than misoprostol alone but is underutilized in the US. Objective: To describe differences in clinical outcomes after EPL management with mifepristone plus misoprostol vs misoprostol alone using commercial claims data. Design, Setting, and Participants: This retrospective cohort study used national insurance claims data from the IBM MarketScan Research Database. Participants included pregnant people (aged 15-49 years) with private insurance who presented with an initial EPL diagnosis between October 1, 2015, and December 31, 2022. Exposures: The primary exposure was the medication used to manage EPL (ie, mifepristone plus misoprostol or misoprostol alone). Other exposures of interest included demographic characteristics and location of service. Main Outcomes and Measures: The primary outcome was subsequent procedural management (eg, uterine aspiration) after EPL diagnosis and medication management. Other outcomes of interest included return visits, hospitalizations, and complications occurring in the subsequent 6 weeks. Descriptive statistics and bivariate analyses were used, and a multivariable logistic regression model was created to examine factors associated with subsequent procedural management. Results: This study included 31 977 patients (mean [SD] age, 32.7 [5.6] years) with claims for EPL who received medication management. Of these patients, 3.0% received mifepristone plus misoprostol and 97.0% received misoprostol alone. Patients who received misoprostol with pretreatment with mifepristone were less likely to have subsequent uterine aspiration (10.5% vs 14.0%; P = .002), and they were also less likely to have subsequent emergency department (ED) visits for EPL (3.5% vs 7.9%; P < .001). In multivariable analysis, use of mifepristone plus misoprostol was associated with decreased odds of subsequent procedural management (adjusted odds ratio, 0.71 [95% CI, 0.57-0.87]). Conclusions and Relevance: The findings of this study suggest that mifepristone is underutilized for the medication management of EPL, but its use is associated with a lower need for subsequent uterine aspiration and a decrease in the number of subsequent visits to an ED. Increasing access to mifepristone for EPL management may decrease health care utilization and expenditures.

Conservative treatment of cesarean scar pregnancy with the combination of methotrexate and mifepristone: A systematic review.

BACKGROUND: Cesarean scar pregnancy (CSP) has become more frequent as a direct consequence of the increased number of cesarean deliveries and the advances in imaging. Although some cases are characterized by spontaneous resolution, unrecognized or mishandled CSP has the potential to cause both fetal and maternal morbidity and mortality. However, due to its infrequency, there is no agreement on the best management. OBJECTIVE: The purpose of this study was to evaluate the safety, the risks and effectiveness of medical therapy with methotrexate and mifepristone to better understand its role in CSP therapy. DESIGN: This study is a systematic review. DATA SOURCES AND METHODS: The electronic databases PubMed, Medline, and Scopus were comprehensively searched until December 2023. Medical Subject Headings terms (Cesarean scar pregnancy) AND (Methotrexate) AND (Mifepristone) AND (Medical Therapy) were used to identify the relevant records. Due to the rarity of this pathology, the studies included are all case reports or case series. The methodological quality of the included studies was assessed using the JBI Critical Appraisal Checklist for case reports. RESULTS: We included in our review a total of seven cases reported in five manuscripts at the end of the screening process. Our review suggests that this type of combination treatment can be considered. The success rate is 71.4%. Treatment seems to be most effective when beta human chorionic gonadotropin (B-hCG) is below 5,000 mUi/ml and when the gestational sac is less than 20 mm. The absence of fetal heartbeat seems to be a positive prognostic factor for a positive outcome. CONCLUSION: Methotrexate and mifepristone administration can be considered as an alternative first-line effective treatment, especially in case of pregnancy with B-hCG <5,000 mUi/ml and when the gestational sac is less than 20 mm. It is important to individualize the management and treatment according to the clinical condition, the patient's age, number of previous cesarean deliveries, willingness to have other children, and the physicians' experience.

Unrecognized Cesarean Scar Pregnancy has the potential to cause both fetal and maternal morbidity and mortality. Methotrexate (MTX) and Mifepristone administration can be considered as an alternative first-line effective treatment especially in case of pregnancy with a low BHCG and when the gestational sac is less than 20 mmCesarean scar pregnancy (CSP) has become more frequent as a direct consequence of the increased number of Cesarean deliveries and the advances in imaging. Unrecognized CSP has the potential to cause both fetal and maternal morbidity and mortality. However, there is no agreement on the best management. The purpose of this study was to evaluate the safety, the risks, and effectiveness of medical therapy with methotrexate and mifepristone. The electronic databases PubMed, Web of Science, and Scopus were comprehensively searched until December 2023. We included in our review a total of seven cases reported in five5 manuscripts at the end of the screening process. Our review suggests that this type of combination treatment can be considered. The success rate is 71.4%. Treatment seems to be most effective when B-hCG is below 5000 mUi/ml and when the gestational sac is less than 20 mm. methotrexate (MTX) and mifepristone administration can be considered as an alternative first-line effective treatment.

Abortion Restrictions Threaten Miscarriage Management In The United States.

Miscarriage and abortion require similar clinical management. Restrictions placed on abortion threaten the quality of miscarriage care, a policy spillover that affects many Americans. We combined vital statistics with life-table parameters to estimate that 1,034,000 miscarriages occur annually, including nearly 400,000 in US states with abortion bans. Attempts to restrict mifepristone access further threaten miscarriage management.

Early metabolic and transcriptomic regulation in rainbow trout (Oncorhynchus mykiss) liver by 11-deoxycorticosterone through two corticosteroid receptors pathways.

Cortisol hormone is considered the main corticosteroid in fish stress, acting through glucocorticoid (GR) or mineralocorticoid (MR) receptor. The 11-deoxycorticosterone (DOC) corticosteroid is also secreted during stress and could complement the cortisol effects, but this still not fully understood. Hence, we evaluated the early transcriptomic response of rainbow trout (Oncorhynchus mykiss) liver by DOC through GR or MR. Thirty juvenile trout were pretreated with an inhibitor of endogenous cortisol synthesis (metyrapone) by intraperitoneal injection in presence or absence of GR (mifepristone) and MR (eplerenone) pharmacological antagonists for one hour. Then, fish were treated with a physiological DOC dose or vehicle (DMSO-PBS1X as control) for three hours (n = 5 per group). We measured several metabolic parameters in plasma, together with the liver glycogen content. Additionally, we constructed cDNA libraries from liver of each group, sequenced by HiseqX Illumina technology and then analyzed by RNA-seq. Plasma pyruvate and cholesterol levels decreased in DOC-administered fish and only reversed by eplerenone. Meanwhile, DOC increased liver glycogen contents depending on both corticosteroid receptor pathways. RNA-seq analysis revealed differential expressed transcripts induced by DOC through GR (448) and MR (1901). The enriched biological processes to both were mainly related to stress response, protein metabolism, innate immune response and carbohydrates metabolism. Finally, we selected sixteen genes from enriched biological process for qPCR validation, presenting a high Pearson correlation (0.8734 average). These results describe novel physiological effects of DOC related to early metabolic and transcriptomic responses in fish liver and differentially modulated by MR and GR.

Glucocorticoid signaling mediates stress-induced migraine-like behaviors in a preclinical mouse model.

BACKGROUND: Stress is one of the most common precipitating factors in migraine and is identified as a trigger in nearly 70% of patients. Responses to stress include release of glucocorticoids as an adaptive mechanism, but this may also contribute to migraine attacks. Here, we investigated the role of glucocorticoids on stress-induced migraine-like behaviors. METHODS: We have shown previously that repeated stress in mice evokes migraine-like behavioral responses and priming to a nitric oxide donor. Metyrapone, mifepristone, and corticosterone (CORT) were used to investigate whether CORT contributes to the stress-induced effects. Facial mechanical hypersensitivity was evaluated by von Frey testing and grimace scoring assessed the presence of non-evoked pain. We also measured serum CORT levels in control, stress, and daily CORT injected groups of both male and female mice. RESULTS: Metyrapone blocked stress-induced responses and priming in male and female mice. However, repeated CORT injections in the absence of stress only led to migraine-like behaviors in females. Both female and male mice showed similar patterns of serum CORT in response to stress or exogenous administration. Finally, administration of mifepristone, the glucocorticoid receptor antagonist, prior to each stress session blocked stress-induced behavioral responses in male and female mice. CONCLUSIONS: These findings demonstrate that while CORT synthesis and receptor activation is necessary for the behavioral responses triggered by repeated stress, it is only sufficient in females. Better understanding of how glucocorticoids contribute to migraine may lead to new therapeutic opportunities.

ClassIIb histone deacetylase participates in perioperative neurocognitive disorders in elderly mice via HSP90/GR signaling pathway.

OBJECTIVE: Multiple factors contribute to the development of perioperative neurocognitive disorders (PND). This study was designed to investigate whether Histone Deacetylase 6 (HDAC6) was involved in the formation of postoperative cognitive dysfunction in elderly mice by regulating the degree of acetylation of heat shock protein (HSP90) and related protein functions and quantities. METHODS: C57BL/6 J male mice were randomly divided into six groups: control naive (group Control), anesthesia (group Anesthesia), splenectomy surgery (group Surgery), splenectomy surgery plus dissolvent (group Vehicles), splenectomy surgery plus the inhibitor ACY-1215 (group Ricolinostat), and splenectomy surgery plus the inhibitor RU-486(group Mifepristone). After the mice were trained for Morris Water Maze (MWM) test for five days, anesthesia and operational surgery were carried out the following day. Cognitive function was assessed on the 1st, 3rd and 7th days post-surgery. The hippocampi were harvested on days 1, 3, and 7 post-surgeries for Western blots and ELISA assays. RESULTS: Mice with the splenectomy surgery displayed the activation of the hypothalamic-pituitary-adrenal axis (HPA-axis), marked an increase in adrenocorticotropic hormone (ACTH), glucocorticoid, mineralocorticoid at the molecular level and impaired spatial memory in the MWM test. The hippocampus of surgical groups showed a decrease in acetylated HSP90, a rise in glucocorticoid receptor (GR)-HSP90 association, and an increase in GR phosphorylation and translocation. HDAC6 was increased after the surgical treated. Using two specific inhibitors, HDAC6 inhibitor Ricolinostat (ACY-1215) and GR inhibitor Mifepristone (RU-486), can partially mitigate the effects caused by surgical operation. CONCLUSIONS: Abdominal surgery may impair hippocampal spatial memory, possibly through the HDAC6-triggered increase in the function of HSP90, consequently strengthening the negative role of steroids in cognitive function. Targeting HDAC6- HSP90/GR signaling may provide a potential avenue for the treatment of the impairment of cognitive function after surgery.

First dose of misoprostol administration at home or in hospital for medical abortion between 12-22 gestational weeks in Sweden (PRIMA): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Medical abortion after 12 gestational weeks often requires a stay in hospital. We hypothesised that administering the first misoprostol dose at home could increase day-care procedures as compared with overnight care procedures, shorten inpatient stays, and improve patient satisfaction. METHODS: This multicentre, open-label, randomised controlled trial was done at six hospitals in Sweden. Participants were pregnant people aged 18 years and older who were undergoing medical abortion at 85-153 days of pregnancy. Randomisation was done in blocks 1:1 to mifepristone administered in-clinic followed by home administration or hospital administration of the first dose of misoprostol. Allocation was done by opening of opaque allocation envelopes. Due to the nature of the intervention, masking was not feasible. Between 24-48 h after mifepristone 200 mg, the participants administered 800 µg of misoprostol either at home 2 h before admission to hospital or in hospital. The primary outcome was the proportion of day-care procedures (defined as abortion completed in <9 h). The intention-to-treat analysis included all participants randomly assigned to receive the study drug and who had known results for the primary outcome. Individuals who received any treatment were included in the safety analyses. This trial is registered at ClinicalTrials.gov, NTC03600857, and EudraCT, 2018-000964-27. FINDINGS: Between Jan 8, 2019, and Dec 21, 2022, 457 participants were randomly assigned to treatment groups. In the intention-to-treat-population, 220 participants were assigned to the home group and 215 to the hospital group. In the home group, 156 (71%) of 220 participants completed the abortion as day-care patients, compared with 99 (46%) of 215 in the hospital group (difference 24·9%, 95% CI 15·4-34·3; p<0·0001). In total, 97 (22%) of 444 participants in the safety analysis had an adverse event. Seven (2%) of 444 participants aborted after mifepristone only. Two (1%) of 220 in the home group aborted after the first dose of misoprostol, before hospital admission. INTERPRETATION: Home administration of misoprostol significantly increases the proportion of day-care procedures in medical abortion after 12 gestational weeks, offering a safe and effective alternative to in-clinic protocols. FUNDING: Region Västra Götaland, Hjalmar Svensson's Fund, the Gothenburg Society of Medicine, Karolinska Institutet-Region Stockholm, and The Swedish Research Council.

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.

Abortion Stigma as a Barrier to Mifepristone Use among Obstetrician-Gynecologists in Alabama for Early Pregnancy Loss.

OBJECTIVES: The objective of our study was to identify and characterize barriers to mifepristone use among obstetrician-gynecologists (OB-GYNs) for early pregnancy loss in a southern US state. METHODS: In this qualitative study, we conducted semistructured interviews with 19 OB-GYNs in Alabama who manage early pregnancy loss. The interviews explored participants' knowledge of and experience with mifepristone use for miscarriage management and abortion, along with barriers to and facilitators of clinical mifepristone use. The interviews were coded by multiple study staff using inductive and deductive thematic coding. RESULTS: Nearly all of the interviewees identified abortion-related stigma as a barrier to mifepristone use. Interviewees often attributed stigma to a lack of knowledge about the clinical use of mifepristone for early pregnancy loss. The stigmatization of mifepristone due to its association with abortion was related to religious and political objections. Many interviewees also described stigma associated with misoprostol use. Although providers believed that mifepristone use for abortion would not be accepted in their practice, most believed that mifepristone could be used successfully for miscarriage management after practice-wide education on its use. CONCLUSIONS: Mifepristone is strongly associated with abortion stigma among OB-GYNs in Alabama, which is a barrier to its use for miscarriage management. Interventions to decrease abortion stigma and associated stigma surrounding mifepristone are needed to optimize early pregnancy loss care.

Risk of teratogenicity in continued pregnancy after gestational exposure to mifepristone and/or misoprostol: a systematic review and meta-analysis.

PURPOSE: This meta-analysis aimed to comprehensively assess the teratogenic risk to offspring associated with continuing pregnancy after administering mifepristone and/or misoprostol during gestation. METHODS: We conducted a systematic search of multiple databases, including PubMed, Web of Science, Embase, Cochrane, CNKI, and CBM, from their inception to February 2024, with no language restrictions. We included cohort and case-control studies that analyzed the teratogenic effects of mifepristone and/or misoprostol on fetuses and newborns. Quality assessment was performed using the Newcastle-Ottawa Scale (NOS). The odds ratios (OR) from individual studies were combined using meta-analysis. Sensitivity testing and heterogeneity analysis were conducted. RESULTS: A total of 13 studies were eligible for inclusion, comprising 5193 cases of congenital malformations and 12,232 controls. CONCLUSION: Our findings indicated that the use of misoprostol during early pregnancy increased the risk of congenital abnormalities in offspring (OR = 2.69; 95% CI: 1.57-4.62). However, the potential teratogenic effect of mifepristone during pregnancy cannot be ruled out. Additionally, the use of mifepristone and/or misoprostol has been linked to a higher risk of certain congenital anomalies, such as hydrocephalus (OR = 3.41; 95% CI: 1.17-9.97), Möbius syndrome (OR = 26.48; 95% CI: 11.30-62.01), and terminal transverse limb defects (OR = 10.75; 95% CI: 3.93-29.41). (PROSPERO, CRD42024522093, 03182024).

The Success of Mifepristone and Misoprostol in the Management of Early Pregnancy Loss at a Community Hospital: A Prospective Study.

OBJECTIVES: This prospective single-arm study was conducted to understand the expulsion rate of the gestational sac in the management of early pregnancy loss (EPL). METHODS: We recruited 441 participants; 188 met the eligibility criteria. Participants were 18 years of age and older who experienced a confirmed EPL (<12 weeks gestational age) defined by an intrauterine pregnancy with a non-viable embryonic or anembryonic gestational sac with no fetal heart activity. Participants were given 200 mg of mifepristone pre-treatment orally followed by 2 doses of misoprostol 800 µg vaginally after 24 and 48 hours. Participants were seen in follow-up on day 14 to confirm the absence of a gestational sac, classified as treatment success. For failed treatment (defined by retained gestational sac), we offered expectant management or a third dose of misoprostol and/or dilatation and curettage. We followed all participants for 30 days. We collected data on overtreatment for retained products of conception and hospital admissions for adverse events. RESULTS: Overall, 181 participants followed the protocol and 169 (93.3%) participants had a complete expulsion of the gestational sac by the second visit (day 14). Twelve (6.6%) failed the treatment and 1 had an adverse event of heavy vaginal bleeding requiring dilatation and curettage. Despite the expulsion of the gestational sac, 29 cases (17.1%) at subsequent follow-up were diagnosed as retained products of conception based on ultrasound assessment of thickened endometrium. CONCLUSIONS: Pretreatment with mifepristone followed by 2 doses of misoprostol with a 14-day follow-up resulted in a high expulsion rate and is a safe management option for EPL.

Congenital and Fetal Effects After Mifepristone Exposure and Continuation of Pregnancy: A Systematic Review.

Mifepristone is an anti-progestational drug that is the first component of the standard medical abortion regimen. For women who take mifepristone and then do not take misoprostol, which is the second component of the medical abortion regimen, it is possible that their pregnancy may continue to live birth. Since mifepristone is commonly used for medical abortion up to 9-10 weeks gestation, any adverse or teratogenic effects on the developing embryo/fetus must be considered, given exposure during the critical time of its development and organogenesis. Toxicology and teratology reports have cited studies demonstrating teratogenic effect of mifepristone in some animals. Current clinical guidelines for women exposed to mifepristone in the first trimester of pregnancy state that it is not known to be teratogenic based on limited published evidence from humans. The aim of this narrative systematic review was to investigate embryonic/fetal exposure to mifepristone and any association with congenital or fetal anomalies. This study was conducted by systematic searches of health databases from inception to February 2024. The references of relevant citations were manually searched to retrieve any additional citations not captured in database searching. Congenital anomalies and adverse outcomes were encountered at various doses of mifepristone exposure. A number of the congenital anomalies encountered in this review were explained by circumstances other than exposure to mifepristone. The present systematic review did not find data to support mifepristone being implicated as a teratogen.

Support for Mail-Order Pharmacy Dispensing of Mifepristone for Medication Abortion.

According to this study.

A validated HPLC-MS/MS method for the quantification of systemic mifepristone after subcutaneous application in mice.

Mifepristone (RU486, MIF) is a synthetic steroidal hormone with progesterone and glucocorticoid receptor antagonistic characteristics. MIF is commonly used for pharmalogical abortions, but also for the treatment of endometrial and endocrine disorders. The goal of the study was to establish and validate a targeted HPLC-MS/MS method for the quantification of MIF and one of its active metabolites metapristone (MET) in plasma after subcutaneous implantation of slow-release MIF pellets in female BALB/c mice. Additionally, we aimed to apply the analytical method to tissue of several organs to understand the tissue-specific distribution of both analytes after release into systemic circulation. Sample preparation comprised a simple liquid-liquid extraction with diethylether and required 100 µl of plasma or homogenates of approximately 50 mg of tissue. The presented HPLC-MS/MS method showed high sensitivity with baseline separation of MIF, MET, and the internal standard levonorgestrel within a run time of only 8.0 minutes and comparable limits of quantification for plasma and tissue homogenates ranging from 40 pg ml-1 to 105 pg ml-1 for MIF and MET. The presented study is suitable for murine plasma and tissues and can be easily applied to human samples.

Study protocol for a prospective, multicentre study of hypercortisolism in patients with difficult-to-control type 2 diabetes (CATALYST): prevalence and treatment with mifepristone.

INTRODUCTION: Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper c ortisolism in P at ients with Difficult to Control Type 2 Di a betes Despite Receiving Standard-of-Care Therapies: Preva l ence and Treatment with Korl y m® (Mifepri st one) (CATALYST) trial. METHODS AND ANALYSIS: In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%-11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym®). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life. ETHICS AND DISSEMINATION: The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05772169.

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-1ß) 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-1ß 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-1ß), demonstrating an anti-inflammatory role. Furthermore, irrespective of sleep fragmentation, mifepristone increased pro-inflammatory cytokine gene expression in heart (IL-1ß), pre-frontal cortex (IL-1ß), and hypothalamus (IL-1ß). The results provide mixed evidence for pro- and anti-inflammatory functions of corticosterone to regulate inflammatory responses to acute sleep loss.

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.

Medication and procedural abortion uptake during a period of increasing abortion hostility.

Hundreds of state-level abortion restrictions were implemented in the US between 2010 and 2020. Medication abortion was being widely adopted during this same period. Understanding the impact of health policies and political climate will improve the delivery of and access to reproductive healthcare in a period of rapid change. To measure the association between state abortion hostility and mifepristone and procedural abortion rates, we conducted a state-level repeated cross-sectional study using 2010-2020 employer-sponsored insurance claims data from Merative MarketScan. The exposure of interest was a 13-point state-level abortion hostility score based on the presence of policies which either reduce or protect access to abortion. Outcomes of interest were annual mifepristone and procedural abortion claims per 100,000 enrollees. We used a linear mixed model adjusting for urbanicity, age group, and year. We assessed whether temporal trends in abortion claims were modified by state abortion hostility by interacting year with two measurements of abortion hostility: baseline score in 2010 and change from baseline score. We found that median state-level mifepristone claims increased from 20 to 37 per 100,000 included enrollees; meanwhile, median procedural abortions claims decreased from 69 to 20 per 100. For mifepristone, every unit increase in a state's baseline abortion hostility score was associated with 7.5 (CI, -12 to -3.6) fewer mifepristone claims per 100,000 in 2010. For states with baseline hostility and change scores of zero, we did not observe a significant time trend over the 11 year study period. For every unit increase in baseline hostility, the time trend changed by 0.5 fewer claims (CI, -0.8 to -0.2) per 100,000 per year. States with higher baseline abortion hostility had fewer overall abortions, less uptake of mifepristone abortions, and slower decline in procedural abortions between 2010 and 2020. Changes in hostility from new restrictions during this time period did not significantly impact claims. Advocates for abortion access must simultaneously attend to individual abortion policies and the overall political climate. Updated research on the relationship between political climate and the evolving clinical landscape of abortion care is needed to inform this work.