Mifepristone regulates macrophage-mediated natural killer cells function in decidua.

Mifepristone has been used for first-trimester abortion and contraception. Nevertheless, its functional mechanism still needs to be elucidated. Decidua tissues were collected from 40 pregnant women who received (20 patients) or did not receive (20 patients) mifepristone. Immunofluorescence was used to analyze the effect of mifepristone on the quantity of CD56 and CD206 in decidua. in vitro assay, NK cells were isolated from decidua tissue and macrophages were induced from THP-1 cells. NK cells were co-cultured with macrophages pre-treated different concentrations of mifepristone (0 nmol/L, 200 nmol/L, 1800 nmol/L, and 25000 nmol/L); the cells' cytotoxicity and migration ability were analyzed using MTT assay and transwell assay, respectively. Si-TGF-ß1, which was utilized to knock down the TGF-ß1 expression in macrophages and human recombinant TGF-ß1 were used to verify whether TGF-ß1 was involved in the mifepristone regulation of NK cells function. The quantity of CD56 and CD206 decreased after mifepristone treatment. Moreover, the NK cells' cytotoxicity and migration ability were significantly increased by macrophages pre-treated with mifepristone in a dose-dependent manner. Moreover, compared with the si-NC group, the MTT absorbance rate of NK cells was significantly increased in the si-TGF-ß1 group and was decreased in the human recombinant TGF-ß1 group. Our data suggest that mifepristone, which regulates NK cells function through macrophages, was associated with the changes in TGF-ß1 secreted by macrophages. This may be one of the mechanisms of mifepristone acting as contraceptive and abortion drugs at the maternal-fetal interface.

Management of pain associated with up-to-9-weeks medical termination of pregnancy (MToP) using mifepristone-misoprostol regimens: expert consensus based on a systematic literature review.

Evidence-based guidelines on the management of pain associated with first-trimester medical abortion are lacking. Most published clinical trials have failed to report on this important aspect of the procedure. The aim of this comprehensive work was to provide clinical advice based on a comprehensive literature review, supplemented by the clinical experience of a group of European experts in case no evidence is available. Pain level ranged from 5 to 8 in 80% of studies where pain was measured on a 0-10 visual analogue scale; severe pain was reported by 20-80% of women. Pain assessment was rarely reported in studies. Pain treatment should be preventive and avoidance of unnecessary uterine contractions should be considered. Analgesic treatment should follow the WHO three-step ladder, starting with the use of NSAIDs and allowing for easily available back-up treatment with weak opioids.

Dosing interval between mifepristone and misoprostol in second and third trimester termination.

OBJECTIVE: To compare several strategies for second trimester labor induction for termination of pregnancy (TOP) using misoprostol and mifepristone and to determine which one is more effective in accelerating the time to delivery. METHOD: This was a retrospective study in which pregnancies that underwent second and third trimester TOP due to fetal anomalies between 2007 and 2017 were classified into a group that received misoprostol alone, a group that received mifepristone followed by misoprostol on the same day, one where misoprostol was given 1 day after mifepristone and one where the medications were administered 2 days apart. The primary outcome measure was the induction to delivery interval. RESULTS: 481 pregnancies fulfilled the inclusion criteria. In 140 cases, mifepristone was not administered. 341 women received mifepristone prior to induction, which was administered on the day of induction in 85 cases, and 1 or 2 days prior to induction in 140 and 19 cases. Median time interval between first induction and delivery was 15.0 (IQR 10.0-24.1) h in case no mifepristone was given and 13.2 (9.7-18.2) h if mifepristone was given on the same day and 9.3 (6.6-14.9) and 10.5 (7.2-22.3) h, if mifepristone was given 1 or 2 days prior to induction. After 24 h, the proportion of terminated pregnancies in each of the four groups was 75.0, 83.5, 93.2 and 78.9%. CONCLUSION: A 1 day interval between mifepristone and misoprostol is more effective in second and third trimester TOP compared to other strategies in terms of reducing the induction to abortion interval.

Prostaglandin-Endoperoxide Synthase 1 Mediates the Timing of Parturition in Mice Despite Unhindered Uterine Contractility.

Cyclooxygenase (COX)-derived prostaglandins stimulate uterine contractions and prepare the cervix for parturition. Prior reports suggest Cox-1 knockout (KO) mice exhibit delayed parturition due to impaired luteolysis, yet the mechanism for late-onset delivery remains unclear. Here, we examined key factors for normal onset of parturition to determine whether any could account for the delayed parturition phenotype. Pregnant Cox-1KO mice did not display altered timing of embryo implantation or postimplantation growth. Although messenger RNAs of contraction-associated proteins (CAPs) were differentially expressed between Cox-1KO and wild-type (WT) myometrium, there were no differences in CAP agonist-induced intracellular calcium release, spontaneous or oxytocin (OT)-induced ex vivo uterine contractility, or in vivo uterine contractile pressure. Delayed parturition in Cox-1KO mice persisted despite exogenous OT treatment. Progesterone (P4) withdrawal, by ovariectomy or administration of the P4-antagonist RU486, diminished the delayed parturition phenotype of Cox-1KO mice. Because antepartum P4 levels do not decline in Cox-1KO females, P4-treated WT mice were examined for the effect of this hormone on in vivo uterine contractility and ex vivo cervical dilation. P4-treated WT mice had delayed parturition but normal uterine contractility. Cervical distensibility was decreased in Cox-1KO mice on the day of expected delivery and reduced in WT mice with long-term P4 treatment. Collectively, these findings show that delayed parturition in Cox-1KO mice is the result of impaired luteolysis and cervical dilation, despite the presence of strong uterine contractions.

Roles of Mifepristone on the Regulation of Cytotoxic Lymphocytes and Regulatory T Cells.

OBJECTIVE: To investigate the immunologic function of mifepristone, which acts as a contraceptive drug at the level of the decidua. SETTING: In our hospital, 60 women (less than 63 days of amenorrhea) volunteered to terminate their pregnancies by the uterine suction evacuation method. Immunohistochemically, the transcription factor forkhead box P3 and granzyme B staining were performed to identify regulatory T cells and cytotoxic lymphocytes (CLs) in all operational subjects. CD8 (cytotoxic T cells marker) and CD56 (natural killer cells marker) staining were further performed in order to characterize the CLs subpopulations. RESULT: A significantly increased number of CLs was found in the decidua treated with mifepristone. CONCLUSION: Mifepristone increases the expression of CLs in the decidua, and it provides new insights into the immunologic function of mifepristone as a drug used for pregnancy termination.

Management of Medical Termination of Pregnancy (MToP) up until the 7th week of gestation in the Czech Republic.

OBJECTIVE: In the Czech Republic (CR), it is possible, to carry out Medical Termination of Pregnancy (MToP) in the 1st trimester since June 2014, in case a woman submits a written request for it and in case the ultrasound examination confirms an intrauterine singleton prosperous pregnancy, between day 42 and 49 of gestation, crown-rump length (CRL) of the embryo 2-9 mm. The aim of the study is to analyze the management of MToP up until the 7th week of gestation in five centres in the CR. DESIGN: Multicenter cohort (prospective) study. SETTING: Department of Obstetrics and Gynecology, Palacky University Olomouc, Faculty of Medicine and Dentistry, University Hospital Olomouc; The Institute for the Care of Mother and Child, Charles University in Prague, Third faculty of Medicine; Department of Gynecology and Obstetrics, Charles University in Prague, First faculty of Medicine, General University Hospital in Prague; Department of Gynecology and Obstetrics, Charles University in Prague, First faculty of Medicine, Hospital Na Bulovce, Prague; Department of Gynecology and Obstetrics, Masaryk University, Faculty of Medicine, University Hospital Brno. METHODS: In 2014-2016, a total of 1820 pregnant women requested MToP. The diagnosis of an intrauterine singleton prosperous pregnancy was set by transvaginal ultrasound, CRL 2-9 mm. MToP was carried out by combination of mifepristone (600 mg orally) and misoprostol (400 mcg orally) within 48 hours. MToP follow up (exclusion of ongoing pregnancy) after 2-3 weeks was carried out by transvaginal ultrasound as well. RESULTS: In 11.0% of women (201/1820) who requested MToP, CRL > 9 mm, unprosperous, multiple or ectopic pregnancy was diagnosed. In the remaining 1619 women MToP was carried out, but in 221 cases (13.7%) at least one additional pre-first visit was needed before the diagnosis of intrauterine singleton prosperous pregnancy CRL 2-9 mm could be established, in 19 cases (1.2%) two pre-first visits and in 5 cases (0.3%) even three. Gestational age was 42-49 days (average 47.1, median 47), the women were 14-47 years of age (average 30.7, median 30). In 20.8% of women (336/1619) MToP follow up was missed and of the remaining 1283 women, ongoing pregnancy (MToP failure) was diagnosed in 1.6% (24/1283), incomplete abortion in 6.5% (83/1283) and complete abortion in 91.9% (1179/1283). A subsequent surgical intervention was carried out in 7.1 % of women (91/1283). CONCLUSION: A medical facility performing MToP in the 1st trimester should develop its own methodology in accordance with the legislation in force, Summaries of Product Characteristics, and recommendations of professional associations. The methodology should also include a method of evaluation of the result and management. The subsequent surgical intervention should only be performed in indicated cases. The main goal of MToP follow up is to exclude ongoing pregnancy (MToP failure), and the patient should be informed in detail about the risks involved and possibilities of their solution, it is necessary to obtain an informed consent.

Progesterone Decreases in vitro Indoleamine 2, 3-dioxygenase Expression in Dendritic and CD4+ Cells from Maternal-Fetal Interface of Rats.

PROBLEM: Several mechanisms contribute to the tolerogenic state observed during pregnancy, such as the activity of the enzyme indoleamine 2, 3-dioxygenase (IDO). This initializes the catabolism of tryptophan, inducing T cells to apoptosis due to its deprivation and by the action of its catabolites in the placental microenvironment. Progesterone plays an important part on immunological tolerance mechanisms during pregnancy; however, there is no evidence it is related to IDO activity. Thus, this study aimed to investigate progesterone influence on the maternal-fetal interface of pregnant Wistar rats, by identifying IDO positive cells by immunophenotyping and flow cytometry under exogenous progesterone supplementation. METHOD OF STUDY: Placenta and embryo cells were cultured and separated into groups that received interferon γ or progesterone, supplemented or not with mifepristone. After 2 and 24 h, these were labeled with an anti-IDO and a series of antibodies specific to leucocytes and progesterone receptor and processed through flow cytometry analysis. RESULTS: Progesterone induced a significant decrease in the expression of IDO in dendritic cells and CD4+ lymphocytes. CONCLUSION: The blocking of progesterone receptor on these cells by mifepristone restored IDO expression levels and may constitute evidence of the participation of this hormone through a direct route in these cells.

Elevated mRNA expression of PGF2α receptor splice variant 2(FP-V2) in human decidua is associated with incomplete mifepristone-misoprostol-induced early medical abortion by regulation of interleukin-8.

OBJECTIVE: The combination of mifepristone and misoprostol is an established method for the induction of early abortion, but 15% of women still experience the unpleasant side effect of incomplete medical abortion. The purpose of this study was to determine whether prostaglandin (PG) F2α receptor (FP) and its two isoforms (FP-V1 and FP-V2) in human decidua are associated incomplete abortion. METHODS: Forty women who underwent medical abortion were recruited. Among them, there were 20 cases of incomplete abortion. The other 20 cases of complete abortion were used as controls. The expression levels of FP, FPV1 and FP-V2 in the decidua between of the two groups was detected by quantitative real-time polymerase chain reaction (PCR). Additionally, FP-V2 was knocked down using specific small interfering RNAs (siRNAs) in the primary cultures of decidual cells. The expression levels of cytokines in FP-V2 knockdown primary decidual cells and control decidual cells were detected by quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA). RESULTS: The FP and FP-V2 mRNA expression in the incomplete group was significantly higher than that in the complete group (p < 0.05). IL-8 was up-regulated by FP-V2 knockdown in primary-cultured decidual cells (p < 0.05). CONCLUSIONS: These results suggested that the elevated expression of FP-V2 in human decidua is significantly associated with incomplete mifepristone-misoprostol-induced early medical abortion and that IL-8 could be lined to this process.

Abscess formation in ovarian endometriomas after failure of mifepristone-induced abortion.

OBJECTIVE: To report a case of abscess formation in bilateral ovarian endometriomas after failure of mifepristone-induced abortion. CASE REPORT: A-36-year-old multiparous woman with bilateral ovarian endometriomas conceived spontaneously and received mifepristone to induce an abortion at 35 days' gestation. Fever and lower abdominal pain occurred 28 days after the abortion. The patient then underwent surgical curettage for an incomplete abortion complicated by endometritis. Her symptoms and signs became aggravated, and computed tomography showed a large ovarian abscess. She underwent laparoscopic drainage of the abscess plus the enucleation of the ovarian endometriomas, and received intravenous antibiotic treatment. She resumed menstruation one month later and was doing well at the 11-month follow-up. CONCLUSION: This case demonstrates the importance of combining antibiotic therapy with mifepristone to induce abortions in women with known ovarian endometriomas.

The expression of thyroid hormone receptors (THR) is regulated by the progesterone receptor system in first trimester placental tissue and in BeWo cells in vitro.

BACKGROUND: Thyroid hormones are essential for the maintenance of pregnancy and a deficiency in maternal thyroid hormones has been associated with early pregnancy losses. The aim of this study was a systematic investigation of the influence of mifepristone (RU 486) on the expression of the thyroid hormone receptor (THR) isoforms THRα1, THRα2, THRß1 and THRß2 on protein and mRNA-level. METHODS: Samples of placental tissue were obtained from patients with mifepristone induced termination of pregnancy (n=13) or mechanical induced termination of normal pregnancy (n=20), each from the 4th to 13th week of pregnancy. Expression of THRα1, THRα2, THRß1 and THRß2 was analysed on protein level by immunohistochemistry and on mRNA level by real time RT-PCR (TaqMan). The influence of progesterone on THR gene expression was analysed in the trophoblast tumour cell line BeWo by real time RT-PCR (TaqMan). RESULTS: Nuclear expression of THRα1, THRα2 and THRß1 is downregulated on protein level in mifepristone (RU 486) treated villous trophoblast tissue. In decidual tissue, we found a significant downregulation only for THRα1 in mifepristone treated tissue. On mRNA level, we also found a significantly reduced expression of THRA but no significant downregulation for THRB in placental tissue. The gene THRA encodes the isoform THRα and the gene THRB encodes the isoform THRß. The majority of cells expressing the thyroid hormone receptors in the decidua are decidual stromal cells. In addition, in vitro experiments with trophoblast tumour cells showed that progesterone significantly induced THRA but not THRB expression. CONCLUSIONS: Termination of pregnancy with mifepristone (RU 486) leads to a downregulation of THRα1, THRα2 and THRß1 in villous trophoblasts and in addition to a decreased expression of THRA in placental tissue. Decreased expression of THRα1 induced by RU486 could also be found in the decidua. Therefore inhibition of the progesterone receptor may be responsible for this downregulation. This assumption is supported by the finding, that stimulation of the progesterone receptor by progesterone itself up-regulated THRA in trophoblast cells in vitro.

Prospective study evaluating the effect of mifepristone on E-cadherin expression in villi in early pregnancy.

BACKGROUND: E-cadherin plays an important regulatory role in implantation, embryo development and placentation. This study aimed to determine the effect of mifepristone on E-cadherin expression in human villi in early pregnancy. STUDY DESIGN: Forty healthy women seeking elective pregnancy termination at 5-7 weeks of gestation were recruited. Of these, 22 women chose medical termination (mifepristone-treated group) and took 25mg mifepristone every 12h for 3 days and 600µg buccal misoprostol on the morning of the fourth day. The other 18 women underwent vacuum aspiration (control group). Following collection of villi, E-cadherin protein expression was assessed by immunohistochemical analysis, and E-cadherin mRNA expression was assessed by reverse transcription-polymerase chain reaction. RESULTS: E-cadherin protein expression was significantly higher (p<0.05) in villous cytotrophoblast cells in the mifepristone-treated group compared with the control group. E-cadherin mRNA expression was also significantly higher (p<0.01) in the mifepristone-treated group compared with the control group. CONCLUSION: E-cadherin expression in villi may be involved in mifepristone-induced pregnancy termination.

Safety, efficacy and acceptability of outpatient mifepristone-misoprostol medical abortion through 70 days since last menstrual period in public sector facilities in Mexico City.

Extensive evidence exists regarding the efficacy and acceptability of medical abortion through 63 days since last menstrual period (LMP). In Mexico City's Secretariat of Health (SSDF) outpatient facilities, mifepristone-misoprostol medical abortion is the first-line approach for abortion care in this pregnancy range. Recent research demonstrates continued high rates of complete abortion through 70 days LMP. To expand access to legal abortion services in Mexico City (where abortion is legal through 12 weeks LMP), this study sought to assess the efficacy and acceptability of the standard outpatient approach through 70 days in two SSDF points of service. One thousand and one women seeking pregnancy termination were enrolled and given 200 mg mifepristone followed by 800 µg misoprostol 24-48 hours later. Women were asked to return to the clinic one week later for evaluation. The great majority of women (93.3%; 95% CI: 91.6-94.8) had complete abortions. Women with pregnancies ≤ 8 weeks LMP had significantly higher success rates than women in the 9th or 10th weeks (94.9% vs. 90.5%; p = 0.01). The difference in success rates between the 9th and 10th weeks was not significant (90.0% vs. 91.2%; p = 0.71). The majority of women found the side effects (82.9%) and the use of misoprostol (84.4%) to be very acceptable or acceptable. This study provides additional evidence supporting an extended outpatient medical abortion regimen through 10 weeks LMP.

Baicalin can attenuate the inhibitory effects of mifepristone on Wnt pathway during peri-implantation period in mice.

Wnts are considered as important factors in uterus developmental process and embryo implantation. Baicalin has been demonstrated to possess tocolytic properties. In order to investigate the effect of baicalin on the Wnt signaling pathway during the peri-implantation, pregnant Kuming mice were randomly divided into four groups: control group, baicalin group administered with 40mg/kg BW of baicalin through an intragastric gavage on day 2 to 7 of the pregnancy (Pd2-Pd7), mifepristone group treated with 4mg/kg BW of mifepristone, an abortifacient agent, via subcutaneous administration on Pd4, and baicalin+mifepristone group treated with their combination. The concentrations of the implantation-related steroid hormones (progesterone and estradiol) in the blood serum were measured with RIA. The gene and protein expression levels of the important molecules of the Wnt pathway (Wnt4, LRP6, Dkk1 and ß-catenin) in the endometrium were detected with RT-PCR and western blot, respectively. The results showed that baicalin decreased (P<0.05) the estradiol levels on Pd4-Pd8 and increased (P<0.05) the progesterone levels on Pd3-Pd8. Mifepristone increased (P<0.05) the estradiol levels on Pd5-Pd8 and decreased (P<0.05) the progesterone levels on Pd6-Pd8. Compared with the control group, baicalin increased the gene and protein expression levels of Wnt4, LRP6 and ß-catenin (P<0.05) and decreased the gene and protein expression levels of Dkk1 (P<0.05) during the middle-to-late stage of the experiment in mice uterine tissue. Baicalin alleviated the mifepristone-induced increase or decrease in the serum levels of progesterone and estradiol, and the gene or protein expression levels of Wnt4, LRP6 and ß-catenin. The tocolytic properties tocolysis of baicalin may be realized through regulating the levels of estrogen/progesterone and the important components of canonical Wnt signaling pathway during the embryo implantation process intervened with the subcutaneous administration of mifepristone in the mice.

Assessment of effects of mifepristone administration to lactating mice on the development and fertility of their progeny.

AIM: Mifepristone, a synthetic steroid compound that induces abortion, was recently found to potentially pass into human milk. This study aimed to determine the effects of mifepristone administration to lactating mice on the development and reproduction of their progeny. METHODS: Lactating mice were gavage fed with mifepristone (8 mg/kg) daily for 4 days either from days 1-4 or from days 7-10 of lactation; controls received only peanut oil. Growth, mortality rate, organ weight to bodyweight ratio, sex hormone at 20, 40 and 60 days, fertility of these F1 progeny and litter size, sex ratio and mortality rate of the second generation were recorded. RESULTS: No significant differences were observed in the average bodyweight, mortality rate of the female or male pups, and organ coefficient of uterus and ovaries of females in adulthood in comparison with the controls. However, the organ coefficient of testis at day 20 and 40 and testosterone concentration at day 60 were increased in male pups. Moreover, the reproductive capacity of the F1 pups was unaffected by 4 days exposure to mifepristone via their mother's milk: time to birth of F2 pups, litter size, sex ratio and mortality rate were similar to control F1 pups. CONCLUSION: The study showed that treating lactating mice with 8 mg/kg mifepristone influenced only the organ coefficient of testis at day 40 and the testosterone concentration in male pups at day 60, however, it did not affect the development and fertility of female and male pups.

Interplacental uterine expression of genes involved in prostaglandin synthesis during canine pregnancy and at induced prepartum luteolysis/abortion.

BACKGROUND: In the non-pregnant dog, ovarian cyclicity is independent of a uterine luteolysin. This is in contrast to pregnant animals where a prepartum increase of luteolytic PGF2α occurs, apparently originating in the pregnant uterus. Recently, the placenta as a source of prepartum prostaglandins (PGs) was investigated, indicating fetal trophoblast cells as the likely main source. However, the possible contribution of uterine interplacental tissues to the production of these hormones has not yet been thoroughly examined in the dog. METHODS: Several key factors involved in the production and/or actions of PGs were studied: cyclooxygenase 2 (COX2, PTGS2), PGF2α-synthase (PGFS/AKR1C3), PGE2-synthase (PGES), and the respective receptors FP (PTGFR), EP2 (PTGER2) and EP4 (PGTER4), 15-hydroxyprostaglandin dehydrogenase (HPGD), PG-transporter (PGT, SLCO2A1) and progesterone receptor. Their expression and localization patterns were assessed by Real Time PCR and immunohistology in the interplacental uterine sites from pregnant dogs during the pre-implantation period (days 8-12), post-implantation (days 18-25), mid-gestation (days 35-40) and during antigestagen-induced luteolysis/abortion. RESULTS: Whereas only low COX2 expression was observed in uterine samples at all the selected time points, expression of PGFS/AKR1C3 strongly increased post-implantation. A gradual increase in PGES-mRNA expression was noted towards mid-gestation. FP-mRNA expression decreased significantly with the progression of pregnancy until mid-gestation. This was associated with clearly detectable expression of HPGD, which did not change significantly over time. The expression of FP and EP2-mRNA decreased significantly over time while EP4-mRNA expression remained unaffected. The antigestagen-treatment led to a significant increase in expression of COX2, PGES, EP2 and PGT (SLCO2A1) mRNA. COX2 was localized predominantly in the myometrium. The expression of PGFS/AKR1C3, which was unchanged, was localized mostly to the surface luminal epithelium. The expression of EP4, PGT and HPGH did not change during treatment, they were co-localized with PGES and EP2 in all uterine compartments. CONCLUSIONS: The data clearly demonstrate the basic capability of the canine pregnant uterus to produce and respond to PGs and suggests their functions both as local regulatory factors involved in the establishment and maintenance of pregnancy, as well as potential contributors to the process of parturition, supporting the myometrial contractility associated with fetal expulsion.

Effects of steroid ablation and progestin replacement on the transcriptome of the primate corpus luteum during simulated early pregnancy.

Previous microarray analyses indicated that a portion of the transcriptome in the macaque corpus luteum (CL) of the menstrual cycle was regulated indirectly by luteinizing hormone via the local actions of steroid hormones, notably progesterone (P). The current study was designed to investigate this concept in the CL of early pregnancy by analyzing chorionic gonadotrophin (CG)-regulated genes that are dependent versus independent of local steroid action. Exogenous human chorionic gonadotropin treatment simulating early pregnancy (SEP) began on Day 9 of the luteal phase in female rhesus monkeys with and without concurrent administration of the 3-ß-hydroxysteroid dehydrogenase inhibitor trilostane (TRL) with or without the synthetic progestin R5020. Compared with SEP treatment alone, TRL altered 50 mRNA transcripts on Day 10, rising to 95 on Day 15 (P<0.05, ≥2-fold change in gene expression). Steroid-sensitive genes were validated; notably effects of steroid ablation and P replacement varied by day. Expression of some genes previously identified as P-regulated in the macaque CL during the menstrual cycle were not significantly altered by steroid ablation and P replacement during CG exposure in SEP. These data indicate that the majority of CG-regulated luteal transcripts are differentially expressed independently of local steroid actions. However, the steroid-regulated genes in the macaque CL may be essential during early pregnancy, based on previous reports that TRL treatment initiates premature structural regression of the CL during SEP. These data reinforce the concept that the structure, function and regulation of the rescued CL in early pregnancy differs from the CL of the menstrual cycle in primates.

Mifepristone: a potential clinical agent based on its anti-progesterone and anti-glucocorticoid properties.

Nowadays, unwanted pregnancy is a major globe tragedy for millions of women, associated with significant direct and indirect costs, no matter for individuals or society. The progesterone receptor antagonist steroid, mifepristone has been widely and effectively using throughout the world for medical abortion, but to a lesser extent for emergency contraception. In this review, we hope to explore the role of mifepristone as a contraceptive, particularly for emergency contraception. Studies of mifepristone have also been expanding to the fields of endometriosis and uterine fibroids. Furthermore, this initially considered reproductive medicine has been investigated in some psychotic diseases and various disorders of hypercortisolism, because of its glucocorticoid receptor antagonism. Mifepristone was approved suitable for patients with hyperglycemia secondary to Cushing's syndrome by the United States Food and Drug Administration (FDA) in 2012. The aim of this article is to review published reports on the anti-progesterone and anti-glucocorticoid properties of mifepristone as a clinical agent. There is a new insight into systematically describing and evaluating the potential efficiency of mifepristone administrated in the field of endocrine and neuroendocrine, not only in obstetrics and gynecology.

Mifepristone: current knowledge and emerging prospects.

The first clinically available antiprogestin, mifepristone has generated immense interest in the research community since its' discovery in 1980. Mifepristone is a synthetic orally active steroid with potent antiglucocorticoid, antiprogestogen and a weak anti-androgen activity, used primarily for termination of pregnancy. It acts as a competitive receptor antagonist at the progesterone receptor in the presence of progesterone, and acts as a partial agonist in the absence of progesterone. Extensive research has been carried out regarding its' antiprogestogen activity for use in medical abortion. Lately other medical uses of mifepristone are being explored like for induction of labour in late preg- nancy, as oestrogen free oral contraceptive and for treatment of endometriosis, uterine fibroids, ovarian cancer, prostate cancer, meningiomas, Cushing's syndrome and major psychotic depression.

Regulation of α3-containing GABAA receptors in guinea-pig adrenal medullary cells by adrenal steroids.

GABA is thought to function as a paracrine factor in adrenal medullary (AM) cells. Thus, we electrophysiologically and immunologically examined the properties of GABAA receptors (GABAARs) in guinea-pig AM cells. Bath application of GABA produced an inward current at -60 mV in a dose-dependent manner with an EC50 of 32.3 µM. This GABA-induced current was enhanced by allopregnanolone at concentrations of 0.01 µM and more. A prior exposure to allopregnanolone resulted in a decrease in an EC50 for GABA in activating GABAARs. The GABA-induced current was suppressed by Zn(2+) in a dose-dependent manner with an IC50 of 18 µM, whereas it was enhanced by 100 µM La(3+). The benzodiazepine analog diazepam was three times more potent than zolpidem in enhancing the GABA current, and it was also augmented by L-838,417, which has no action on α1-containing GABAARs. The GABAAR α3, but not α1, and γ2 subunits were immunologically detected at the cell periphery. The expression of α3 subunits in PC12 cells was enhanced by glucocorticoid activity. The results indicated that GABAARs in guinea-pig AM cells mainly comprise α3, ß, and γ2 subunits and are enhanced by allopreganalone and glucocorticoids may play a major role in the expression of α3 subunits.

Modulation of free corticotrophin-releasing hormone, adrenal and placental steroid hormone levels induced by mifepristone during pregnancy.

UNLABELLED: Mifepristone is a progesterone receptor antagonist widely used in obstetrics. The aim of the study was to focus on free corticotrophin-releasing hormone (CRH) and also describe modulation of adrenal and placental steroid hormone concentrations induced by mifepristone. METHODS: Twenty-six women were enrolled in the study. They received mifepristone for termination of pregnancy. Maternal blood samples were retrieved before administration of mifepristone (600 mg) and 48 h after, just before induction of labor. Bound and free CRH levels were determined in maternal blood concomitantly with cortisol, estriol, progesterone and SDHEA levels. Also paired fetal cord blood samples were collected. RESULTS: Maternal plasmatic CRH level did not change after mifepristone absorption but free CRH increased significantly (0.500 ± 0.326 vs. 0.388 ± 0.303 ng/ml, p = 0.040). A significant decrease of progesterone was observed (83.6 ± 49.3 vs. 95.6 ± 54.9 ng/ml, p = 0.001) with a lower progesterone/estriol ratio (26.9 ± 15.7 vs. 40.7 ± 31.1, p = 0.004). There was a strong association between maternal and fetal free CRH (r² = 0.675, p = 0.001), cortisol (r² = 0.570, p = 0.019), and positive but modest correlation for progesterone (r² = 0.341, p = 0.046) and estriol (r² = 0.379, p = 0.025) levels. CONCLUSION: Mifepristone has an effect on free CRH level and changes the estriol-progesterone balance.