Mifepristone Antagonization with Progesterone to Avert Medication Abortion: A Scoping Review.

The safety and efficacy of mifepristone antagonization with progesterone to avert medication abortion, also known as abortion pill rescue, is a subject of vigorous debate. Two prominent medical associations have taken positions that either entirely reject or fully support its use. This scoping review aimed to gain insight into the safety and efficacy of its use. Analysis of 16 studies showed that the continuing pregnancy rate after ingesting mifepristone alone is ≦25 percent for gestational ages ≦49 days. Analysis of four studies showed that two-thirds of the women who changed their minds and received progesterone after initiating their medication abortion with mifepristone could safely continue their pregnancies. There is no increased maternal or fetal risk from using bioidentical progesterone in early pregnancy. If a woman has already taken mifepristone for her medication abortion and then changes her mind, timely supplementation with progesterone may allow her pregnancy to continue. The conclusion that mifepristone antagonization with progesterone is a safe and effective treatment has implications for medication abortion informed consent. Summary: Two-thirds of the women who changed their minds and received progesterone after initiating their medication abortion with mifepristone could safely continue their pregnancies. If a woman has already taken mifepristone for her medication abortion and then changes her mind, timely supplementation with progesterone may allow her pregnancy to continue. Physicians should disclose this treatment option to their patients at the time of informed consent.

Investigating the role of the central melanocortin system in stress and stress-related disorders.

The melanocortinergic neural circuit, known for its influence on energy expenditure and feeding behavior, also plays a role in stress and stress-induced psychiatric disorders, including anxiety and depression. The major contribution is given by the melanocortin-4 receptor (MC4R) subtype, highly expressed in brain regions involved in the control of stress responses. Furthermore, the MC4R appears to profoundly affect the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and it has been also highlighted a functional and anatomical interaction with the corticotropin-releasing factor (CRF), an important mediator of stress and stress-related behaviors. The MC4R agonists seem to exacerbate stress-inducing anxiety- and depressive-like behavior, while MC4R antagonists have been demonstrated to mitigate such disorders, as shown in several preclinical behavioral tests. The evidence collected in the present review suggests that the melanocortin system, through the MC4R, could possibly modulate behavioral responses to stress, suggesting the use of MC4R antagonists as a possible novel treatment for anxiety and depression induced by stress.

Combined antagonist treatment of glucocorticoid and mineralocorticoid receptor does not affect weight loss of fasting rainbow trout but inhibits a fasting-induced elevation of cortisol secretion.

The gastrointestinal system of fish reacts rapidly to food deprivation. The relative masses of digestive organs and activities of digestive enzymes decrease within days of fasting. This is believed to be an energy-conserving strategy as the metabolic cost of maintaining digestive capacity is high. Cortisol is known for its role in energy mobilization following stress exposure, and prolonged elevated cortisol levels have been shown to reduce growth rates in fish. Fish experiencing chronic cortisol elevations show structural changes to their digestive tissues and overall reductions in relative digestive tissue masses. In fish fasting for prolonged periods, circulating cortisol levels have been reported to be downregulated, upregulated, or unchanged compared to feeding fish. This study aimed to investigate if RU486 and spironolactone, antagonists of the glucocorticoid receptor (GR), and mineralocorticoid receptor (MR), respectively, alone or in combination affect circulating cortisol levels during prolonged starvation. In addition, we tested the effects of blocking GR and MR, on the down-regulation of relative digestive tissue mass during starvation, and its effects on weight loss. Three treatment groups of rainbow trout were intraperitoneally implanted with either GR, MR, or GR and MR blockers. A fourth group was implanted with cortisol, while a fifth group served as a control. All treatment groups were sampled over a course of four weeks of food deprivation and compared against each other and fed control fish at day 0 of the trial. Starvation for 2 weeks and longer significantly increased circulating cortisol levels in all groups except for the group implanted with GR and MR antagonists. Loss of body mass occurred most rapidly during the first week of starvation. Spironolactone treatment resulted in significantly reduced loss of mass during the first week, however, over the following weeks, no differences in mass loss were observed in the groups implanted with blockers, while cortisol-treated fish showed the highest decrease in body mass over time. Relative digestive tissue mass decreased in all groups but apparently, the fasting-induced elevation in plasma cortisol levels did not affect the relative weight loss of digestive tissues as no differences were observed between control fish and GR + MR antagonist treated fish. Very high cortisol levels caused by cortisol treatment however caused a faster decrease in the relative mass of some digestive organs, particularly the stomach.

Mifepristone blocks the anxiolytic- and antidepressant-like effects of allopregnanolone in male rats.

BACKGROUND: Allopregnanolone (3α, 5α-tetrahydroprogesterone) is an inhibitory neurosteroid synthesized from progesterone via 5α-reductase activity in the brain and has anxiolytic, antidepressant, sedative, anticonvulsant, and analgesic activity. Altered levels of allopregnanolone cause anxiety, depression, premenstrual syndrome, and psychiatric disorders. Although allopregnanolone exerts most of its actions by modulating GABAA receptor, NMDA receptor, BDNF expression, and PXR activity, a recent study showed its effects are blocked by mifepristone on lordosis behavior which indicates the involvement of progestin or glucocorticoid receptors in the effects of allopregnanolone since mifepristone blocks both these receptors. However, whether these receptors are involved in acute anxiolytic or antidepressant-like effects is unknown. METHODS: Adult male Wistar rats were used to study whether the prior administration of mifepristone would alter the effects of allopregnanolone in the elevated plus maze (EPM) and forced swim test (FST) was evaluated. RESULTS: 10 mg/Kg dose of allopregnanolone increased percent open arm entries in the EPM, whereas 3 mg/Kg dose of allopregnanolone decreased percent immobility in the FST. Mifepristone administration resulted in a U-shaped response in the FST (with 1 mg/Kg, s.c., decreasing the immobility time) without significantly impacting the behavior in the EPM. In combination studies, mifepristone blocked the anxiolytic and antidepressant effects of allopregnanolone. CONCLUSION: The current study provides evidence for the first time that progestin or glucocorticoid receptors are involved in the acute anxiolytic and antidepressant effects of allopregnanolone. Understanding the mechanism of action of allopregnanolone will help us design better therapeutic strategies to treat neuropsychiatric diseases such as depression and anxiety.

The Impact of Mouse Preterm Birth Induction by RU-486 on Microglial Activation and Subsequent Hypomyelination.

Preterm birth (PTB) represents 15 million births every year worldwide and is frequently associated with maternal/fetal infections and inflammation, inducing neuroinflammation. This neuroinflammation is mediated by microglial cells, which are brain-resident macrophages that release cytotoxic molecules that block oligodendrocyte differentiation, leading to hypomyelination. Some preterm survivors can face lifetime motor and/or cognitive disabilities linked to periventricular white matter injuries (PWMIs). There is currently no recommendation concerning the mode of delivery in the case of PTB and its impact on brain development. Many animal models of induced-PTB based on LPS injections exist, but with a low survival rate. There is a lack of information regarding clinically used pharmacological substances to induce PTB and their consequences on brain development. Mifepristone (RU-486) is a drug used clinically to induce preterm labor. This study aims to elaborate and characterize a new model of induced-PTB and PWMIs by the gestational injection of RU-486 and the perinatal injection of pups with IL-1beta. A RU-486 single subcutaneous (s.c.) injection at embryonic day (E)18.5 induced PTB at E19.5 in pregnant OF1 mice. All pups were born alive and were adopted directly after birth. IL-1beta was injected intraperitoneally from postnatal day (P)1 to P5. Animals exposed to both RU-486 and IL-1beta demonstrated microglial reactivity and subsequent PWMIs. In conclusion, the s.c. administration of RU-486 induced labor within 24 h with a high survival rate for pups. In the context of perinatal inflammation, RU-486 labor induction significantly decreases microglial reactivity in vivo but did not prevent subsequent PWMIs.

Determination of Mifepristone (RU-486) and Its Metabolites in Maternal Blood Sample after Pharmacological Abortion.

The aim of the study was the development and validation of the UHPLC-QqQ-MS/MS method for the determination of mifepristone in human blood as well as the identification and quantification of its metabolites after self-induced pharmacological abortion. The metabolic pathway in humans was proposed after examination of an authentic casework. The fast and simple preanalytical procedure was successfully applied (pH9, tert-butyl-methyl ether). The validation parameters of the method were as follows: limit of quantification: 0.5 ng/mL; coefficients of determination: >0.999 (R2), intra- and inter-day accuracy and precision values did not exceed ± 13.2%. The recovery and matrix effect were in the range of 96.3−114.7% and from −3.0 to 14.7%, respectively. Toxicological analysis of the mother's blood (collected the day after the pregnancy termination) revealed the presence of five compounds: mifepristone (557.4 ng/mL), N-desmethyl-mifepristone (638.7 ng/mL), 22-OH-mifepristone (176.9 ng/mL), N,N-didesmethyl-mifepristone (144.5 ng/mL) and N-desmethyl-hydroxy-mifepristone (qualitatively). To our knowledge, the study presented in this paper is the first report on the concentrations of mifepristone and its metabolites in maternal blood samples after performing a self-induced abortion. The established UHPLC-QqQ-MS/MS method is suitable for forensic toxicological analysis as well as in terms of clinical toxicology in future investigations (examination of pharmacokinetics, bioavailability and metabolism of RU-486).

Glutamine synthetase regulation by dexamethasone, RU486, and compound A in astrocytes derived from aged mouse cerebral hemispheres is mediated via glucocorticoid receptor.

Glucocorticoids (GCs) regulate astrocyte function, while glutamine synthetase (GS), an enzyme highly expressed in astrocytes, is one of the most remarkable GCs-induced genes. GCs mediate their effects through their cognate glucocorticoid receptor (GRα and GRß isoforms); however, the mechanism via which these isoforms regulate GS activity in astrocytes remains unknown. We used dexamethasone (DEX), a classical GRα/GRß agonist, RU486, which is a specific GRß ligand, and Compound A, a known "dissociated" ligand, to delineate the mechanism via which GR modulates GS activity. Aged Mouse Cerebral Hemisphere astrocytes were treated with DEX (1 µM), RU486 (1 nM-1 µM) or compound A (10 µM), alone or in combination with DEX. GS activity and expression, GR isoforms (mRNA and protein levels), and GRα subcellular trafficking were measured. DEX increased GS activity in parallel with GRα nuclear translocation. RU486 increased GS activity in absence of GRα nuclear translocation implicating thus a role of GRß-mediated mechanism compound A had no effect on GS activity implicating a GRα-GRE-mediated mechanism. None of the compounds affected whole-cell GRα protein content. DEX reduced GRα and GRß mRNA levels, while RU486 increased GRß gene expression. We provide evidence that GS activity, in astrocytes, is regulated via GRα- and GRß-mediated pathways with important implications in pathological conditions in which astrocytes are involved.

Deaths and Severe Adverse Events after the use of Mifepristone as an Abortifacient from September 2000 to February 2019.

OBJECTIVES: Primary: Analyze the Adverse Events (AEs) reported to the Food and Drug Administration (FDA) after use of mifepristone as an abortifacient. Secondary: Analyze maternal intent after ongoing pregnancy and investigate hemorrhage after mifepristone alone. METHODS: Adverse Event Reports (AERs) for mifepristone used as an abortifacient, submitted to the FDA from September 2000 to February 2019, were analyzed using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAEv3). RESULTS: The FDA provided 6158 pages of AERs. Duplicates, non-US, or AERs previously published (Gary, 2006) were excluded. Of the remaining, there were 3197 unique, US-only AERs of which there were 537 (16.80%) with insufficient information to determine clinical severity, leaving 2660 (83.20%) Codable US AERs. (Figure 1). Of these, 20 were Deaths, 529 were Life-threatening, 1957 were Severe, 151 were Moderate, and 3 were Mild.The deaths included: 9 (45.00%) sepsis, 4 (20.00%) drug toxicity/overdose, 1 (5.00%) ruptured ectopic pregnancy, 1 (5.00%) hemorrhage, 3 (15.00%) possible homicides, 1 (5.00%) suicide, 1 (5.00%) unknown. (Table 1).Retained products of conception and hemorrhage caused most morbidity. There were 75 ectopic pregnancies, including 26 ruptured ectopics (includes one death).There were 2243 surgeries including 2146 (95.68%) D&Cs of which only 853 (39.75%) were performed by abortion providers.Of 452 patients with ongoing pregnancies, 102 (22.57%) chose to keep their baby, 148 (32.74%) had terminations, 1 (0.22%) miscarried, and 201 (44.47%) had unknown outcomes.Hemorrhage occurred more often in those who took mifepristone and misoprostol (51.44%) than in those who took mifepristone alone (22.41%). CONCLUSIONS: Significant morbidity and mortality have occurred following the use of mifepristone as an abortifacient. A pre-abortion ultrasound should be required to rule out ectopic pregnancy and confirm gestational age. The FDA AER system is inadequate and significantly underestimates the adverse events from mifepristone.A mandatory registry of ongoing pregnancies is essential considering the number of ongoing pregnancies especially considering the known teratogenicity of misoprostol.The decision to prevent the FDA from enforcing REMS during the COVID-19 pandemic needs to be reversed and REMS must be strengthened.

HIV-1 Tat Dysregulates the Hypothalamic-Pituitary-Adrenal Stress Axis and Potentiates Oxycodone-Mediated Psychomotor and Anxiety-Like Behavior of Male Mice.

Human immunodeficiency virus (HIV) is associated with co-morbid affective and stress-sensitive neuropsychiatric disorders that may be related to dysfunction of the hypothalamic-pituitary-adrenal (HPA) stress axis. The HPA axis is perturbed in up to 46% of HIV patients, but the mechanisms are not known. The neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat), may contribute. We hypothesized that HPA dysregulation may contribute to Tat-mediated interactions with oxycodone, a clinically-used opioid often prescribed to HIV patients. In transgenic male mice, Tat expression produced significantly higher basal corticosterone levels with adrenal insufficiency in response to a natural stressor or pharmacological blockade of HPA feedback, recapitulating the clinical phenotype. On acute exposure, HIV-1 Tat interacted with oxycodone to potentiate psychomotor and anxiety like-behavior in an open field and light-dark transition tasks, whereas repeated exposure sensitized stress-related psychomotor behavior and the HPA stress response. Pharmacological blockade of glucocorticoid receptors (GR) partially-restored the stress response and decreased oxycodone-mediated psychomotor behavior in Tat-expressing mice, implicating GR in these effects. Blocking corticotrophin-releasing factor (CRF) receptors reduced anxiety-like behavior in mice that were exposed to oxycodone. Together, these effects support the notion that Tat exposure can dysregulate the HPA axis, potentially raising vulnerability to stress-related substance use and affective disorders.

Regulation of the Abortion Drug RU 486: The Collision of Politics, Ethics and Morals in Australia.

The abortion drug RU 486 is widely available across the developed world, and its benefits and efficacy for women have been well established over the 40 years since its development. However, access to RU 486 for women in Australia has been a vexed issue since the mid-1990s. Because of pro-life politics under the Howard Government, importation of the drug into Australia was severely hampered, resulting in Australia lagging behind the rest of the developed world in access to medical abortions. This article highlights the history of RU 486, the current state of abortion laws in Australia and the issues that the politics of the 1990s still cause for Australian women who seek a medical abortion (especially those living remotely). Finally, it proposes some options that could alleviate some of the difficulties faced by those who seek access to RU 486.

Dexamethasone induces primary amnion epithelial cell senescence through telomere-P21 associated pathway†.

Dexamethasone (Dex), a corticosteroid hormone, is used during the perinatal period to help fetal lung and other organ development. Conversely, Dex-induced cell proliferation has been associated with accelerated aging. Using primary amnion epithelial cells (AECs) from term, not in labor, fetal membranes, we tested the effects of Dex on cell proliferation, senescence, and inflammation. Primary AECs treated with Dex (100 and 200 nM) for 48 h were tested for cell viability (crystal violet dye exclusion), cell cycle progression and/or type of cell death (flow cytometry), expression patterns of steroid receptors (glucocorticoid receptor, progesterone receptor membrane component 1&2), inflammatory mediators (IL-6 and IL-8), and telomere length (quantitative RT-PCR). Mechanistic mediators of senescence (p38MAPK and p21) were determined by western blot analysis. Dex treatment did not induce AEC proliferation, cell cycle, influence viability, or morphology. However, Dex caused dependent telomere length reduction and p38MAPK-independent but p21-dependent (confirmed by treatment with p21 inhibitor UC2288). Senescence was not associated with an increase in inflammatory mediators, which is often associated with senescence. Co-treatment with RU486 produced DNA damage, cell cycle arrest, and cellular necrosis with an increase in inflammatory mediators. The effect of Dex was devoid of changes to steroid receptors, whereas RU486 increased GR expression. Dex treatment of AECs produced nonreplicative and noninflammatory senescence. Extensive use of Dex during the perinatal period may lead to cellular senescence, contributing to cellular aging associated pathologies during the perinatal and neonatal periods.

Corticosteroids significantly increase cystatin C levels in the plasma by promoting cystatin C production in rats.

Background: Several studies have shown that non-renal factors such as corticosteroids may increase plasma cystatin C levels without affecting kidney function. However, the mechanisms underlying this are unclear. We hypothesized that corticosteroids may increase cystatin C levels in the plasma by promoting its production in tissues. In the present study, we aimed to test our hypothesis in rats by investigating the effect of corticosteroids on cystatin C production in tissues and the glomerular filtration rate (GFR), as measured by the gold standard method (i.e., inulin clearance). Results: Dexamethasone treatment was associated with much higher concentrations of cystatin C in all organ tissue homogenates tested. Dexamethasone increased plasma cystatin C levels in rats, without any decrease in renal inulin clearance. The impact of dexamethasone on plasma and organ tissue cystatin C levels was abolished by RU486, indicating the effect was glucocorticoid receptor-mediated. Conclusions: Our study provides direct evidence that corticosteroids may increase cystatin C levels in the plasma by promoting its production, without any decrease in GFR.

Glucocorticoid receptor involvement in goose (Anas cygnoides) pituitary somatotroph differentiation induced by glucocorticoids during embryonic development.

1. In this study, geese (Anas cygnoides) embryonic pituitary cells were cultured in vitro to determine if glucocorticoids could induce growth hormone (GH) expression and to investigate the molecular mechanisms involved in this process. 2. On embryonic day 15 (e15) and e20 the pituitary cells were treated with corticosterone (CORT), membrane impermeable bovine serum albumin-conjugate corticosterone (CORT-BSA), dexamethasone (DEX), and a glucocorticoid receptor (GR) antagonist (RU486) to detect responsiveness of somatotrophs to glucocorticoids. 3. Treatment with CORT, CORT-BSA, and DEX for as little as 6 h increased the percentage of GH-positive cells (P < 0.01) and increased GH mRNA expression (P < 0.01) in e15 goose pituitary cells compared to the control. CORT significantly increased the level of GH protein secreted from cultured e15 goose embryonic pituitary cells, and CORT-BSA increased GH secretion from e20 goose embryonic pituitary cells. 4. A significant increase was observed in the glucocorticoid receptor in GR transcription levels (P < 0.01) with CORT, CORT-BSA, and DEX treatment. Furthermore, the CORT-stimulated GH mRNA expression was completely negated by pre-treatment with RU486. 5. These findings demonstrate that glucocorticoids can stimulate somatotroph differentiation in vitro, as characterised by enhanced GH protein secretion andmRNA expression in cultured geese embryonic pituitary cells. The membrane GR was involved in pituitary somatotroph differentiation induced by glucocorticoids during the embryonic development of geese.

A novel therapeutic approach for treatment of catamenial epilepsy.

Many women with epilepsy experience perimenstrual seizure exacerbation, referred to as catamenial epilepsy. There is no effective treatment for this condition, proposed to result from withdrawal of neurosteroid-mediated effects of progesterone. A double-blind, multicenter, phase III, clinical trial of catamenial epilepsy has failed to find a beneficial effect of progesterone. The neurosteroid-mediated effects of progesterone have been extensively studied in relation to catamenial epilepsy; however, the effects mediated by progesterone receptor activation have been overlooked. We determined whether progesterone increased excitatory transmission in the hippocampus via activation of progesterone receptors, which may play a role in regulating catamenial seizure exacerbation. In a double-blind study using a rat model of catamenial epilepsy, we found that treatment with RU-486, which blocks progesterone and glucocorticoid receptors, significantly attenuated neurosteroid withdrawal-induced seizures. Furthermore, progesterone treatment as well as endogenous rise in progesterone during estrous cycle increased the expression of GluA1 and GluA2 subunits of AMPA receptors in the hippocampi, and enhanced the AMPA receptor-mediated synaptic transmission of CA1 pyramidal neurons. The progesterone-induced plasticity of AMPA receptors was blocked by RU-486 treatment and progesterone also failed to increase AMPA receptor expression in progesterone receptor knockout mice. These studies demonstrate that progesterone receptor activation regulates AMPA receptor expression and may play a role in catamenial seizure exacerbation.

Repetitive restraint stress changes spleen immune cell subsets through glucocorticoid receptor or ß-adrenergic receptor in a stage dependent manner.

Immune system is sensitive to stress. Spleen is the largest peripheral immune organ innervated with sympathetic nerves and controlled by adrenomedullary system in the body. However, the alterations and mechanism of spleen immune cell subsets caused by repetitive restraint stress (RRS) is poorly understood. In this study, we found that RRS reduced spleen index in mice, and induced an expansion of white pulp and involution of the red pulp. Meanwhile, the percentage of CD3+CD8+ T lymphocytes, CD11b+F4/80+ macrophages, CD11b+Ly-6G-Ly-6Chi monocytic myeloid derived suppressor cells (mMDSCs) and CD11b+Ly-6G+Ly-6Cint granulocytic myeloid derived suppressor cells (gMDSCs) in spleen were significantly changed by RRS. Mechanistically, we found that the expression of norepinephrine (NE) and ß-adrenergic receptor (ß-AR) in spleen were up-regulated after 21 days of RRS, but not 7 days. The expression of corticosterone (CORT) and glucocorticoid receptor (GR) in spleen were up-regulated after 7 days of RRS but were lower after 21 days of RRS, even though they were still higher than that in mice without stress. By treating the stressed mice with RU486 (antagonist of GR) or propranolol (antagonist of ß-AR), we demonstrated that GR was responsible for the changes of spleen induced by 7 days of RRS and ß-AR was for 21 days of RRS. Our data suggest that RRS changes spleen immune cell subsets through GR or ß-AR in a stage dependent manner.

Lordosis facilitated by GPER-1 receptor activation involves GnRH-1, progestin and estrogen receptors in estrogen-primed rats.

The present study assessed the participation of membrane G-protein coupled estrogen receptor 1 (GPER-1) and gonadotropin releasing hormone 1 (GnRH-1) receptor in the display of lordosis induced by intracerebroventricular (icv) administration of G1, a GPER-1 agonist, and by unesterified 17ß-estradiol (free E2). In addition, we assessed the participation of both estrogen and progestin receptors in the lordosis behavior induced by G1 in ovariectomized (OVX), E2-benzoate (EB)-primed rats. In Experiment 1, icv injection of G1 induced lordosis behavior at 120 and 240min. In Experiment 2, icv injection of the GPER-1 antagonist G15 significantly reduced lordosis behavior induced by either G1 or free E2. In addition, Antide, a GnRH-1 receptor antagonist, significantly depressed G1 facilitation of lordosis behavior in OVX, EB-primed rats. Similarly, icv injection of Antide blocked the stimulatory effect of E2 on lordosis behavior. In Experiment 3, systemic injection of either tamoxifen or RU486 significantly reduced lordosis behavior induced by icv administration of G1 in OVX, EB-primed rats. The results suggest that GnRH release activates both estrogen and progestin receptors and that this activation is important in the chain of events leading to the display of lordosis behavior in response to activation of GPER-1 in estrogen-primed rats.

Comparative transcriptome profiling and characterization of gene expression for ovarian differentiation under RU486 treatment.

17α, 20ß-dihydroxypregn-4-en-3-one (17α, 20ß-DP, DHP), a teleost specific biologically active progestin, has been proved to play a critical role in oocytes maturation, ovulation and spermiation. RU486 (Mifepristone, an antagonist of progestin receptor) has been applied in contraceptives, abortion and hormone therapy in clinical medicine. To get further insights into the molecular mechanisms of nuclear progestin receptor (Pgr) activated ovarian differentiation and maintenance, we conducted comparative gonadal transcriptome analysis, and investigated histological and transcriptional differences using 4 months after hatching (mah) RU486-treated XX and control XX/XY Nile tilapia (Oreochromis niloticus). DESeq analysis identified 7148 DEGs (differentially expressed genes) between RU486-treated and control XX gonads, while merely 442 DEGs were screened between the gonads of RU486-treated XX and control XY fish highlighting that RU486 treatment set forwards masculinity in XX fish. Comprehensive analysis of gene hierarchical clustering revealed that RU486 treatment in XX fish resulted in robust changes of gene expression profiles. In comparison with XX group, female-dominant genes were significantly repressed in RU486 treated XX fish gonads. Moreover, most parts of down-regulated genes in wild type female were evidently up-regulated genes in RU486-treated XX fish gonads. Comparing with control XY group, the majority of male-dominant genes represent a high level of expression. However, RU486-treatment led to an up-regulation of a cluster genes specifically which showed relative lower expression in both control XX and XY group. RU486-treatment mediated global changes of gene expression profiles in steroidogenesis, germ cell differentiation and follicular cell trans-differentiation were verified by quantitative PCR. Both morphological and immunohistochemistry results further proved that RU486 treatment initiates testicular-like gonads development in XX fish via simultaneously enhancing the male responsive genes and suppressing the female-dominant genes. Moreover, RU486 treatment caused significant decline of fshr, lhr and increase of ars. Taken together, our data confirms blocking of DHP physiology by RU486 treatment induces masculinization in XX gonad preferably via repressing of gonadotropin physiology, germ cell differentiation and promoting follicular trans-differentiation in teleosts.

RU486 Reverses Emotional Disorders by Influencing Astrocytes and Endoplasmic Reticulum Stress in Chronic Restraint Stress Challenged Rats.

AIMS: To investigate the effect of RU486 (mifepristone) on emotional disorders in chronic restraint stress-induced rats and to explore the mechanisms of that phenomenon. METHODS: For this purpose, 80 healthy male Sprague Dawley rats were randomly divided into four groups: the normal group (Con group, The Con group members received no treatment, eating and drinking freely), the chronic restraint stress group (CRS group, normal Sprague Dawley rats treated with chronic restraint stress, 6 h/day for 21days), the propylene glycol group (CRS+propylene glycol) and the RU486 group (CRS+RU486). RU486 or propylene glycol was administered 30 mins before each CRS procedure. Twenty-four hours after CRS exposure, we investigated the effects of CRS on the anxiety-like behavior using an elevated plus-maze (EPM). To explore the mechanisms of RU486 on anxiety, we measured the expression of glial fibrillary acid protein (GFAP) and ß-subunit of S100 (S100ß) via immunohistochemistry and western blot analysis. Apoptosis was demonstrated by flow cytometry. In addition, endoplasmic reticulum (ER) stress markers, glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and Cysteine aspartic acid specific protease-12 (Caspase-12), were detected by western blot analysis. RESULTS: Compared to the control group, rats in the CRS and propylene glycol group showed decreased exploratory behavior on the open arms during EPM testing, and these reductions were accompanied by significantly reduced GFAP and S100ß expression, increased apoptosis and GRP78, CHOP, and caspase-12 expression in the amygdala. However, RU486 increases the exploratory behavior and reverses the changes of GFAP, S100ß, GRP78, CHOP, and caspase-12 and protects cells against apoptosis. CONCLUSIONS: Taken together, these data suggest that exposure to chronic restraint stress decreases the number of astrocytes and induces apoptosis and ER stress in the amygdala, which are possible causes for psychiatric disorders. RU486 can significantly ameliorate abnormal behaviors in CRS-induced anxiety model rats. The protective effects of RU486 could be attributed to its anti-ER stress, anti-apoptosis and astrocyte increasing effects.

Abortifacient metapristone (RU486 derivative) interrupts CXCL12/CXCR4 axis for ovarian metastatic chemoprevention.

Recent global epidemiological studies revealed the lower ovarian cancer death from long-term use of oral contraceptives. However, the underlying mechanism of action is not clear. Here, we use the abortifacient metapristone (RU486 derivative) to test the hypothesis that the contraceptives might interrupt CXCL12/CXCR4 chemokine axis to inhibit ovarian cancer metastasis. Metapristone at concentrations (

Maternal care modulates the febrile response to lipopolysaccharide through differences in glucocorticoid receptor sensitivity in the rat.

Early life adversity increases the risk for later infection. The febrile response is a potent mechanism to combat infection. We found that variations in maternal care influence the febrile response to 50µg/kg lipopolysaccharide (LPS) challenge in adult male rats. Offspring from low-licking/grooming (LG) mothers had an increased febrile response compared to offspring from high-LG mothers challenged with LPS. Low-LG offspring had reduced plasma IL-6 at one and two hours post challenge compared to high-LG offspring. IL-6 gene expression in the anterior hypothalamus was induced following LPS challenge in low-LG offspring but not in high-LG offspring at two hours post challenge. Occupancy of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) to the IL-6 promoter region in the anterior hypothalamus was greater in low-LG offspring treated with LPS than in high-LG offspring. These findings suggest greater activation of thermoregulatory neurons in the anterior hypothalamus of low-LG compared to high-LG offspring following LPS challenge. Low-LG offspring had greater plasma corticosterone levels following LPS challenge and they had enhanced glucocorticoid receptors (GR) in the spleen compared to high-LG offspring. Enhanced glucocorticoids and glucocorticoid receptor sensitivity associated with reduced IL-6 induction early post challenge in low-LG offspring. Challenge with RU-486 prior to LPS challenge eliminated differences in the febrile response between offspring of high and low-LG mothers. Individual differences in GR sensitivity may modulate differences in the febrile response to LPS challenge, exerting a long-term influence on the capacity to recover from infection.