Clinical Update on Uses for Mifepristone in Obstetrics and Gynecology.

Importance: Mifepristone (RU-486) is a selective progesterone receptor modulator that has antagonist properties on the uterus and cervix. Mifepristone is an effective abortifacient, prompting limitations on its use in many countries. Mifepristone has many uses outside of induced abortion, but these are less well known and underutilized by clinicians because of challenges in accessing and prescribing this medication. Objectives: To provide clinicians with a history of the development of mifepristone and mechanism of action and safety profile, as well as detail current research on uses of mifepristone in both obstetrics and gynecology. Evidence Acquisition: A PubMed search of mifepristone and gynecologic and obstetric conditions was conducted between January 2018 and December 2021. Other resources were also searched, including guidelines from the American College of Obstetricians and Gynecologists and the Society of Family Planning. Results: Mifepristone is approved by the Food and Drug Administration for first-trimester medication abortion but has other off-label uses in both obstetrics and gynecology. Obstetric uses that have been investigated include management of early pregnancy loss, intrauterine fetal demise, treatment of ectopic pregnancy, and labor induction. Gynecologic uses that have been investigated include contraception, treatment of abnormal uterine bleeding, and as an adjunct in treatment of gynecologic cancers. Conclusions and Relevance: Mifepristone is a safe and effective medication both for its approved use in first-trimester medication abortion and other off-label uses. Because of its primary use as an abortifacient, mifepristone is underutilized by clinicians. Providers should consider mifepristone for other indications as clinically appropriate.

Network pharmacology-based study on immunomodulatory mechanism of danggui-yimucao herb pair for the treatment of RU486-induced abortion.

ETHNOPHARMACOLOGICAL RELEVANCE: The Danggui-Yimucao herb pair (DY) is a classic combination in Chinese herbal formulas, consisting of the root of Angelica sinensis (Oliv.) Diels and the aerial parts of Leonurus japonicus Houtt. DY first appeared in "Zhulinsi fuke mifang" in the Jin Dynasty, and it has a long history as a drug for the treatment of abortion. However, its underlying immunomodulatory mechanisms involved are still unclear. AIM OF THE STUDY: In this study, network pharmacology and pharmacological experiments were used to explore the role and mechanism of DY in the treatment of medical abortion. MATERIALS AND METHODS: Network pharmacology was used to establish the relationship between the components of DY and abortion-related targets, and to enrich important pathways and biological process for verification. ELISA was used to assess progesterone levels. Flow cytometry was used to detect the degree of differentiation of Th1/Th2 cells. Immunohistochemical methods and qPCR were used to measure the expression levels of T-bet, GATA-3 and IL-4. RESULTS: Through the prediction analysis of network pharmacology, we found that key pathway for DY treatment of abortion, such as anemia, pelvic infection, immune disorders, and coagulation disorders, was Th1/Th2 cell differentiation pathway. The pharmacological results revealed that DY greatly corrected the imbalance of Th cell subsets in abortion mice, significantly inhibited the differentiation of Th2 cells, and resulted in an increase in the Th1/Th2 ratio. In addition, the concentration of progesterone in the serum of mice after abortion was significantly reduced. We also found that DY upregulated spleen T-bet and downregulated IL-4 gene expression in mice. Besides, immunohistochemical results showed that DYE could up-regulate T-bet but inhibit GATA-3 expression. CONCLUSIONS: Our results showed that after RU486-induced abortion, progesterone and Th1/Th2 paradigm were disordered in mice, but DY could make mice recover more quickly, which indicated that DY had great development value in immunoregulation.

Embedding similarities between embryos and circulating tumor cells: fundamentals of abortifacients used for cancer metastasis chemoprevention.

BACKGROUND: The global epidemiological studies reported lower cancer risk after long-term use of contraceptives. Our systematic studies demonstrated that abortifacients are effective in preventing cancer metastases induced by circulating tumor cells (CTCs). However, the molecular and cellular mechanisms by which abortifacients prevent CTC-based cancer metastases are almost unknown. The present studies were designed to interdisciplinarily explore similarities and differences between embryo implantation and cancer cell adhesion/invasion. METHODS: Biomarker expressions on the seeding embryo JEG-3 and cancer MCF-7 cells, as well as embedding uterine endometrial RL95-2 and vascular endothelial HUVECs cells were examined and compared before and after treatments with 17ß-estradiol plus progesterone and abortifacients. Effects of oral metapristone and mifepristone on embryo implantation in normal female mice and adhesion/invasion of circulating tumor cells (CTCs) in BALB/C female mice were examined. RESULTS: Both embryo JEG-3 and cancer MCF-7 cells expressed high sLex, CD47, CAMs, while both endometrial RL95-2 and endothelial HUVECs exhibited high integrins and ICAM-1. Near physiological concentrations of 17ß-estradiol plus progesterone promoted migration and invasion of JEG-3 and MCF-7 cells via upregulating integrins and MMPs. Whereas, mifepristone and metapristone significantly inhibited migration and invasion of JEG-3 and MCF-7 cells, and inhibited JEG-3 and MCF-7 adhesion to matrigel, RL95-2 cells and HUVECs, respectively. The inhibitions were realized by downregulating sLex, MMPs in JEG-3 and MCF-7 cells, and downregulating integrins in RL95-2 cells and HUVECs, respectively. Mifepristone and metapristone significantly inhibited both embryo implantation and cancer cell metastasis in mice. CONCLUSIONS: The similarities between the two systems provide fundamentals for abortifacients to intervene CTC adhesion/invasion to the distant metastatic organs. The present studies offer the rationale to repurpose abortifacients for safe and effective cancer metastasis chemoprevention.

Cells expressing CD4, CD8, MHCII and endoglin in the canine corpus luteum of pregnancy, and prepartum activation of the luteal TNFα system.

In the dog, knowledge about involvement of the immune system in controlling luteal function is restricted to observations showing a time-dependent invasion of immune cells into the corpus luteum (CL) of non-pregnant bitches. Therefore, this study investigated the presence of CD4-, CD8-, MHCII- and endoglin-expressing cells in CL collected throughout pregnancy from pre-implantation until prepartum luteolysis. Immunohistochemistry and semi-quantitative RT-PCR were applied. The time-dependent expression of CD4, CD8 and endoglin was more strongly related to formation of the CL, whereas MHCII was induced during luteolysis. Next, the luteal expression of TNFα and its receptors, TNFR1 and TNFR2, was analyzed in non-pregnant dogs between days 5-65 after ovulation and during pregnancy. Moreover, the effects of progesterone withdrawal were investigated in mid-pregnant dogs treated with an antigestagen aglepristone. The TNFα system was induced in the early CL of non-pregnant dogs. In pregnant dogs, expression of TNFα did not vary much, contrasting with increased expression of both receptors in the post-implantation period and significantly decreased expression at mid-gestation; prepartum luteolysis was characterized by increased TNFR2 expression. Apart from the downregulated expression of TNFR1, the changes observed following antigestagen treatment resembled those observed during normal prepartum luteolysis. A modulatory function of the TNFα system during formation of the canine CL is suggested, possibly related to the strong accompanying vascularization and luteal infiltration with activated macrophages. Contrasting with the slow luteal regression in non-pregnant dogs, in pregnant animals the upregulation of TNFR2 expression during prepartum luteolysis implies functional involvement of the TNFα system during that time.

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 (

Progesterone and ultrasonographic changes during aglepristone or cloprosternol treatment in queens at 21 to 22 or 35 to 38 days of pregnancy.

Progesterone (P4) is a requirement for pregnancy development. Previous reports observed a maximal value of serum P4 concentration on 21 days after the first mating after which it slowly declines throughout the rest of pregnancy. Ultrasound examination should be performed to ensure that pregnancy interruption is complete. Limited information is available on the ultrasonic appearance of conceptuses during pregnancy termination in cats The objective was to study serum P4 concentration and ultrasonographic changes during aglepristone (ALI) or cloprostenol (CLO) treatment and to evaluate the fertility after treatment. Two experiments (EXP) were carried out to accomplish this aim. Sixty queens, 12- to 36-month-old, were used. On Days 21 to 22 of pregnancy (EXP I) or 35 to 38 of pregnancy (EXP II), queens were divided into three groups (G). Queens in G1 received ALI (10 mg/kg, sc; EXP I, n = 10; EXP II, n = 10) for 2 consecutive days. Queens in G2 received CLO (5 µg/kg, sc; EXP I, n = 10; EXP II = 10) for 3 consecutive days. Queens in G3 received 1 mL of saline solution (PLA, sc; EXP I, n = 10; EXP II = 10). Blood samples were taken before treatment (Day 0) and every day during 10 days after the treatment to measure serum P4 concentrations. Likewise, after treatment, queens were monitored daily by ultrasonography for 10 days and weekly until the end of gestation to obtain gestational sacs measurements (GS), fetal measurements, and fetal biophysical profile. Data were analyzed by ANOVA. Serum P4 concentrations were significantly different on Day 6 (EXP I) and on Day 1 (EXP II) in ALI and CLO groups compared with PLA group (P < 0.05 and P < 0.01; respectively). The ultrasonographic monitoring during treatment allowed assessing changes in the GS and fetal measurements, embryo-fetal viability, and risk of pregnancy loss. In conclusion, the results from this study reported changes in serum P4 concentration and in ultrasonography measurements during pregnancy interruption with ALI or CLO treatment. Also it was observed that ALI and CLO are safe drugs and can preserve posttreatment queen fertility. Therefore, the results obtained in our work will be applied in feline reproduction practice.

Aglepristone: A review on its clinical use in animals.

Aglepristone (RU 46534) is a competitive progesterone antagonist that is indicated for the treatment of various progesterone-dependent physiological or pathologic conditions. Aglepristone has proven to be an effective means of terminating pregnancy in most species. When used to induce parturition, aglepristone was effective in all cases in the bitch, cow, and goat, with no apparent adverse effects on neonatal health or milk production. When used to schedule an elective cesarean section, aglepristone treatment was deemed safe for dams and puppies, providing that the ovulation date had been accurately assessed at the time of breeding. Irrespective of the stage of pregnancy at injection, treatment with aglepristone has no apparent negative effects on subsequent fertility. Aglepristone is also a safe and relatively effective means of treating pyometra. However, given the high level of septic risk and the likelihood of rapid deterioration, such therapy is not recommended in emergency situations. Treatment of feline fibroadenomatosis using aglepristone has given promising results, but repeat treatment may be necessary in cats previously treated with long-acting progestagens. The use of aglepristone in other progesterone-dependent diseases has yet to be fully evaluated but may prove valuable, especially in the treatment of insulin-resistant diabetes mellitus, acromegaly, and the treatment of some vaginal tumors in the bitch.

Abortifacient potential of methanolic extract of Anthocephalus cadamba stem bark in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants possessing abortifacient activity have been used traditionally for a long time in folk medicine. Anthocephalus cadamba, is one such herb that has been known to possess abortifacient potential in ethnobotanical literature, but has not been validated scientifically. MATERIALS AND METHODS: The methanolic extract of Anthocephalus cadamba stem bark (MEAC) was prepared and tested for abortifacient, estrogenic and uterotrophic activity. Pregnant Swiss albino mice were randomized into 5 groups (1-5). Group 1 (negative control) received 0.2% w/v agar, group 2-4 (received extract at the dose of 500, 1000 and 1500mg/kg b.w.) and group 5 received mifepristone at a dose of 5.86mg/kg b.w. respectively, by oral route from 10(th) to 18(th) day post-coitum daily, and various parameters recorded. The uterotrophic bioassay was performed in bilaterally ovariectomized mice dosed from 9(th) to 15(th) day of ovariectomy and change in uterotrophic parameters was observed. RESULTS: Preliminary phytochemical screening revealed presence of glycosides, alkaloids, steroids, saponins, triterpenoids, flavonoids and tannins. No signs of clinical toxicity were observed at any time during the period of treatment. The extract significantly reduced (P<0.05) the number of live fetus, weight and survival ratio of the fetus, number of corpora lutea, progesterone, estradiol and luteinizing hormone whereas the number of dead fetus, number of mice that aborted, percentage vaginal opening and post-implantation loss increased significantly (P<0.05). The estrogenicity experiments showed increase in uterine weight (P<0.05), ballooning of uterus, uterine glucose (P<0.05) and ALP (P<0.001) in extract treated group dose dependently. In addition, the extract also induced vaginal bleeding preceding parturition. CONCLUSION: This study has substantiated the abortifacient potential of the methanolic extract of Anthocephalus cadamba stem bark. The activity was more marked in 1000 and 1500mg/kg b.w. of the extract and was comparable to that of mifepristone. The mechanism of abortion could possibly be through changes in the uterine mileu, altered hormone levels, luteolysis and partly, estrogenicity. This study thus justifies the ethnobotanical claim of MEAC as an abortifacient.

The effects of aglepristone alone and in combination with cloprostenol on hormonal values during termination of mid-term pregnancy in bitches.

This study was designed to assess endocrine changes associated with termination of mid-term pregnancy after use of two different protocols. For this purpose we compared the effects of aglepristone (AGL) alone and in combination with cloprostenol (CLO) on serum concentrations of progesterone (P4), estradiol (E2) and relaxin (RLN) measured at short-term intervals during the abortion period in bitches. Fourteen pregnant bitches between day 25 and 32 of gestation were used in the study. In the AGL group (n=7), aglepristone was administered solely (10mg/kg body weight (BW), subcutaneously, once daily on two consecutive days) whereas in the AGL-CLO group (n=7), aglepristone (dosage as in AGL group) and cloprostenol (1µg/kg BW, subcutaneously, same with aglepristone) were combined. All pregnancies were successfully terminated 5.2±1.6 days after initiation of treatments, which was significant in both groups (P>0.05). At the time of the start of abortion (SA) and the end of abortion (EA), the mean P4 concentrations were 26.6±7.3 and 12.0±6.4ng/ml in AGL group, and 2.7±0.7 and 0.9±0.1ng/ml, in AGL-CLO group, respectively (P<0.01). Serum E2 concentrations were significantly higher (P<0.05) in AGL group at 42, 48, 54h and SA after initiation of treatment. In the AGL-CLO group, serum RLN concentrations did not significantly change from the initiation of treatment to EA (P>0.05). However, markedly higher RLN concentrations (P<0.05) were observed in the AGL group at 48h (1.5±0.7ng/ml) and at SA (1.6±0.5ng/ml). The results of the present study indicate that changes in the hormonal concentrations affect the mechanism of abortion in different ways. Further in depth studies investigating changes in the expression of hormone receptors inside the ovary, endometrium and placenta might be helpful to our understanding of the endocrinological differences observed in this study.

The effect of letrozole with misoprostol for medical termination of pregnancy on the expression of steroid receptors in the placenta.

STUDY QUESTION: What is the effect of letrozole on the expression of steroid receptors in the placentae in cases of termination of pregnancies? SUMMARY ANSWER: The expression of estrogen receptor-α (ERα) and progesterone receptor (PR) transcripts, as well as ERα protein, in placentae was suppressed by letrozole pretreatment in second trimester termination of pregnancy. WHAT IS KNOWN ALREADY: There have been no data in the literature on the effect of letrozole in termination of human pregnancies. STUDY DESIGN, SIZE, DURATION: This study is part of a clinical randomized trial in which 50 subjects were recruited and 44 placentae were collected. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women (n = 50) requesting second trimester abortion between 12 and 20 gestational weeks were randomized to receive either letrozole or placebo pretreatment for 3 days before administration of vaginal misoprostol. Placentae were collected from both groups of women after the abortion. Total RNA from the frozen placenta samples was extracted and subjected to real-time RT-PCR analysis of ERα and estrogen receptor-ß (ERß), PR and glucocorticoid receptor (GR) transcripts. Immunohistochemical studies of ERα, ERß, PR and GR expression, as well as Ki67 and PCNA staining for proliferation, were performed. TUNEL assays were performed to determine the extent of apoptosis. MAIN RESULTS AND THE ROLE OF CHANCE: Real-time RT-PCR demonstrated that the median ERα {3.900 [95% confidence interval (CI): -0.643-8.443] in the letrozole group versus 4.714 (95% CI: 1.776-7.652) in the control group; P = 0.005} and the median PR [0.701 (95% CI: 0.333-1.069) in the letrozole group versus 1.774 (95% CI: 1.07-2.478) in the control group; P = 0.003] were significantly lower in the letrozole group compared with the control group. Furthermore, ERα protein levels, in both syncytiotrophoblasts and cytotrophoblasts but not in villous stromal cells, were significantly reduced [H-score of 113 (95% CI: 103-119) in the letrozole group versus 217 (95% CI: 214-290) in the control group, in syncytiotrophoblasts; 100 (95% CI: 98-105) in the letrozole group versus 210 (95% CI: 200-286) in the control group, in cytotrophoblasts; P = 0.004], while the expression levels of ERß, PR, GR, PCNA, Ki67 and TUNEL were not significantly different between the two groups. LIMITATIONS, REASONS FOR CAUTION: Only the placentae from the second trimester termination of pregnancy were collected in this study. Information from first trimester terminations is still lacking. WIDER IMPLICATIONS OF THE FINDINGS: The results shed some light on the mechanism of action of letrozole pretreatment in termination of pregnancies. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the GRF/RGC and CRCG grants of the University of Hong Kong. TRIAL REGISTRATION NUMBER: HKClinicalTrials.com with trial number HKCTR-695.

Efficacy of Ginkgo biloba on vaginal estrous and ovarian histological alterations for evaluating anti-implantation and abortifacient potentials in albino female mice.

Ginkgo extract, EGb 761 is known as a vasoregulatory variable for the conventional reproduction therapy. EGb 761 was orally administered in 0 (control), 3.7, 7.4, and 14.8 mg/kg bw/day for 28 days (thereafter mated with normal fertile male), from day 1 to day 7 of pregnancy or from the 10th to 18th day of pregnancy, respectively. Vaginal smears were performed daily. On 20th day of pregnancy, the females were killed by cervical dislocation and their kidneys, liver, brain, placenta, spleen and ovaries were removed and weighed. The ovaries were prepared for histological examinations, and then ovarian follicles were counted. Maternal toxicity, estrous cycle, reproductive hormones, ovarian follicle counts, resorption index, implantation index, fetal viability and fetuses, and placenta mean weights were evaluated. There was a dose-dependent ovarian toxic effect of EGb 761. Ovarian follicle counts, resorption index, implantation index, fetal viability were significantly reduced in 14.8 mg/kg bw/day dose. Treatment with 14.8 mg/kg bw/day EGb 761 induced disruption of estrous cycle and caused maternal toxicity, in addition to fetal toxicity. Therefore, the data obtained indicate that Ginkgo biloba extract at 14.8 mg/kg bw/day dose level exhibit toxic effect on reproductive cyclicity and could have anti-implantation and abotifacient properties in female mice.

Effect of plumbagin free alcohol extract of Plumbago zeylanica Linn. root on reproductive system of female Wistar rats.

OBJECTIVE: To assess the effect of plumbagin-free alcohol extract (PFAE) of Plumbago zeylanica Linn. (Plumbaginaceae) (P. zeylanica) root, on female reproductive system and fertility of adult female wistar rats. METHODS: After the oral acute toxicity study, the PFAE was administered at two dose levels to perform the estrous cycle study, anti-implantation and abortifacient activity and hormonal analysis. However, the estrogenic/antiestrogenic activity was evaluated at only one most effective dose. RESULTS: LD(50) cut-off was 5,000 mg/kg body weight. The extract exhibited significant anti-implantation and abortifacient activity at the tested dose levels (300 and 500 mg/kg, p.o.) (P<0.01). The extract dose-dependently decreased the levels of serum progesterone, follicle stimulating hormone and luteinizing hormone, while a dose-dependent increase was observed in the concentration of serum prolactin. The extract did not show any significant changes in structure and function of uterus when given alone, but when given along with ethinyl estradiol, it exhibited significant antiestrogenic activity in immature overiectomized female rats(P<0.001). Biochemical parameters in the serum/blood and haematological parameters did not show appreciable changes throughout and after the course of investigation. However, all the altered parameters returned to normalcy within 30 days following withdrawal of treatment. CONCLUSIONS: All findings suggest that the antifertility activity of extract could possibly be through the changes in the implantation site, altered hormonal levels, prolonged estrous cycle and anti-estrogenic activity. Hence, the extract possesses reversible antifertility activity without adverse toxicity in female rats.

Expression and activity of matrix metalloproteinases in the uterus of bitches after spontaneous and induced abortion.

Aim of this study was to determine the intrauterine activity of matrix metalloproteinases (MMP)-2 and -9 after cessation of the local effect of progesterone. For this purpose, pregnancy was terminated in 10 bitches at mid-gestation with the progesterone receptor antagonist aglepristone (10 mg/kg body weight, sc, Alizine®; Virbac, France) at two subsequent days (group IRA = induced resorption/abortion). The IRA group was divided into two subgroups (Group I, n = 5, days 25-35 of pregnancy; group II, n = 5, days 36-45). Five further bitches were introduced with beginning abortion (group SRA = spontaneous resorption/abortion). Seven healthy bitches between day 25 and 45 of gestation served as controls. After ovariohysterectomy at the end of abortion and between days 25 and 45 of gestation, respectively, the distribution and activity of collagenases were investigated by immunohistochemistry and gelatin zymography. At placental sites, MMP-2 activity in the endometrium was significantly lower in IRA groups than in the SRA group (33.7 ± 11.8% and 39.3 ± 5.4% vs 52.2 ± 10.2%, p < 0.05); however, MMP-2 expression was lowest in the control group (control: 21.4 ± 6.3%; p < 0.01) and similarly in the myometrium (controls: 13.1 ± 2.5%; p < 0.05). MMP-9 activity was also lower in the endometrium and myometrium of the control group in comparison to SRA and IRA groups (11.8 ± 3.2%; p < 0.01 and 28.4 ± 32.8%; p < 0.05). At interplacental sites, the amount of active collagenases in the myometrium was significantly lower in the control group. It is concluded that the blockade of the biological progesterone effect was associated with an increase in activity of both collagenases.

[Abortifacient properties and effect of an misoprostol analogue 11-deoxy-misoprostol on the contractile activity of the rat uterus].

Ethyl ether of 11-deoxy-16-hydroxy-16-metylprostaglandin E1 (11-deoxymisoprostol) increases the contractile activity of uterine horn segments isolated from nonpregnant rats and produces abortive effect when given in a period of time within 1 - 16 days of pregnancy. The drug action is related to a decrease of the progesterone level in ovarian incubates of pregnant rats.

Morphological examination of the corpora lutea from pregnant bitches treated with different abortifacient regimes.

Different abortifacient regimes in dogs were analysed for their effect on the pregnancy corpora lutea (CL), namely, prostaglandin F2a analogue cloprostenol (CLO) combined with dopamine agonist cabergoline (CAB), or progesterone (P4) receptor antagonist aglepristone (AGL). Ovaries were collected after 6-10 days of treatment during first trimester. The CL of the control-group showed strong expression of relaxin (RLX), its receptor RXFP1 and enzymes of steroid biosynthesis (HSD) with high peripheral P4-levels. Whereas RXL, RXFP1 and HSD were lowest expressed in the CLO/CAB-group with a massive degeneration of CL and their blood vessels combined with low peripheral P4-level. The AGL-group showed less extensive CL degeneration and more intensive staining of the examined factors than CLO/CAB. In summary, all examined factors are associated with normal luteal function and are useful tools to stage luteolysis. Although both treatments have the same abortive action, their sequence of events on the CL is different.

Abortifacient potentials of the aqueous extract of Bambusa vulgaris leaves in pregnant Dutch rabbits.

BACKGROUND: There is the claim in the folklore medicine of Nigeria of the use of Bambusa vulgaris leaves as an abortifacient. However, there has not been any scientific evidence in the literature that substantiated or refuted this claim. STUDY DESIGN: Pregnant Dutch rabbits weighing 1.62-1.70 kg were randomized into three groups. Group A (control) was orally administered with 1.85 mL/kg body weight of distilled water (vehicle), thrice daily on Days 18-20 of pregnancy, while Groups B and C were treated like the control group except they received 250 and 500 mg/kg body weight of the aqueous extract of B. vulgaris leaves. RESULTS: Preliminary chemical screening of the aqueous extract of B. vulgaris leaves revealed the presence of alkaloids, tannins, phenolics, glycosides, saponins, flavonoids and anthraquinones. Clinical toxicity symptoms such as respiratory distress, salivation, weight loss, dull eyes, diarrhea, change in the appearance of fur as well as mortality were not observed in the animals at any period of the experiment. The 250 mg/kg body weight of the extract decreased (p<.05) the number of live fetus, whereas the 500 mg/kg body weight produced no live fetus. The 250 and 500 mg/kg body weight of the extract reduced the survival rate of the fetus to 29% and 0%, whereas the same doses produced abortion at the rate of 60% and 100%, respectively. The implantation index and preimplantation loss compared well with the control. Both doses increased the resorption index and postimplantation loss. The extract also decreased the concentrations of serum progesterone, follicle-stimulating and luteinizing hormones. While there was no effect on the weight of the uterus, uterine/body weight ratio, length of the right uterine horn and uterine cholesterol, the alkaline phosphatase activity and glucose concentration decreased significantly. The extract also provoked vaginal opening. CONCLUSION: This study has substantiated the abortifacient potential of the aqueous extract of B. vulgaris leaves. The mechanism of abortion could possibly be through changes in the implantation site, altered hormone levels and, partly, estrogenicity. All these may be attributed, at least, in part to the phytoconstituents.

Effect of mifepristone on the corpus luteum in early pregnancy.

OBJECTIVE: The antiprogestin mifepristone is widely used for medical termination of pregnancy (TOP). Previous studies have suggested that the mechanism of mifepristone is based on its action in the endometrium and myometrium. The aim of this study was to evaluate the possible effects of mifepristone on corpus luteum activity. METHODS: This was a prospective, longitudinal controlled study to which 20 patients undergoing medical TOP (study group) and 20 patients with normal ongoing pregnancy (control group) were recruited. Medical TOP was induced with 200 mg of mifepristone followed by 0.8 mg of misoprostol 2 days later. Three-dimensional ultrasound examinations and hormone assays (progesterone, human chorionic gonadotropin, and 17-hydroxyprogesterone) were performed in both groups on the day of, and 2 days after, administration of mifepristone. Total volume (vascularized + non-vascularized) of the dominant (containing corpus luteum) and non-dominant ovary and serum hormone levels were measured. RESULTS: After administration of mifepristone, a decrease in serum progesterone levels was observed with a simultaneous decrease in the non-vascularized volume of the dominant ovary in the study group. No such changes were observed in the control group. CONCLUSIONS: The observations indicate that, in addition to trophoblastic tissue, the corpus luteum is also the target of mifepristone.

Induction of abortion with aglepristone significantly changed the expression of progesterone and estrogen receptors in canine endometrial stromal cells.

In the present study, resorption/abortion was induced between days 25 and 45 of gestation with aglepristone (group IRA, n=10). The aim was to observe the change in the distribution of progesterone (PR) and estrogen receptors (ER), in comparison to a group of spontaneous resorptions/abortions (group SRA, n=5), and a further group of normal healthy pregnant animals, ovariohysterectomized between days 25 and 45 of gestation (controls, n=7). The receptors were assessed by means of immunohistochemistry (IHC) and RT-PCR, at the placental and interplacental sites of the uterine horn as well as in the corpus uteri. Significant differences were observed between the controls on one side and the groups of resorption/abortion on the other side. The total scores of the progesterone receptors (TPR) in the placental and interplacental part of the uterine horn, was significantly lower in the endometrial stromal cells (ESC) of the control group than in those of the SRA- and IRA-group, respectively (placenta: 5.8 vs. 6.5 and 6.7, p<0.01; interplacental sites: 5.6 vs. 6.6 and 6.6, p<0.05). In contrary, the total scores of the estrogen receptors (TER) at interplacental sites and the corpus uteri, respectively, was significantly higher in the myometrial smooth muscle cells (MSMC) and the ESC (p<0.05) of the controls. We therefore conclude, that the here observed differences between groups point to an up-regulation of TPR- and a down-regulation of TER-scores in endometrial stromal cells at different uterine sites during resorption/abortion, which indicates a special role of these cells.

Mid-gestation pregnancy termination in rabbits by the progesterone antagonist aglepristone.

UNLABELLED: The efficacy of aglepristone treatment to induce abortion in does 15 and 16 days after mating was investigated. The pregnant does were randomly allocated into two groups: For group I, aglepristone was injected twice (10mg/kg, subcutaneously) on days 15 and 16 after mating (n=10); for group II the does got no treatment but the same volume of 0.9% sodium chloride solution was subcutaneously injected at the same days of pregnancy (n=5). RESULTS: group I, termination of pregnancy was successful in all does. The mean interval between the first administration of aglepristone and the beginning of vaginal discharge was 32.4+/-5.6h (range 19-72h). Complete expulsion of all fetuses was observed in four does with first occurrences of vaginal discharge on the same day. The duration between the first occurrence of vaginal discharge to expulsion of all fetuses ranged between 21 and 130h (mean 70.2+/-12.2h). As important side effects, decrease in food consumption during abortion time and irregular mating behaviour (52.3+/-2.0 days/range 46-63) were recorded. But after this time all does were mated again, 8/10 became pregnant and they whelped normal and live kittens. Group II, all does gave birth to live kittens after a mean pregnancy length of 31.2+/-0.37 days (range 30-32 days). The mean serum progesterone (P(4)) concentrations were significantly different between control and treated does after day 20 of pregnancy (P<0.05). The results indicate that aglepristone treatment is effective to induce abortion in does and causes no serious negative effects on further fertility except a short non-receptive period after abortion and short time decrease in food consumption.

Histological changes of the feline cervix, endometrium and placenta after mid-gestational termination of pregnancy with aglepristone.

This study was conducted to investigate endometrial and placental structural changes that occurred in response to mid-gestational termination of pregnancy in queens using aglepristone, a progesterone receptor antagonist. Thirteen European Shorthair pregnant queens were either treated with aglepristone (10 mg/kg body weight; subcutaneously) twice on days 25 and 26 after first mating (am; group I; n = 9), or remained untreated and served as control (group II; n = 4). Queens of group I were ovariohysterectomized between days 30 and 41 am, either at the onset (n = 3) or during (n = 1) abortion and 12 h (n = 1), 24 h (n = 3) or 10 days after abortion (n = 1). Queens of group II were ovariohysterectomized on day 30 am. Tissue was collected from the cervix, and the interplacental zone as well as the paraplacenta/placental girdle of the uterus, subjected to standard histological procedures and evaluated using light microscopy. During abortion, gaps appeared within the paraplacenta and the placental girdle which were filled with blood, leading to an embryo-maternal disconnection. Blood was also observed within the uterine lumen as well as the interstitial mucosal stroma of the cervix and the placental girdle zone and probably originated from damaged venules, whilst arterioles remained intact. As the interval between abortion and surgery increased, the interstitial and luminal haemorrhages became less pronounced and completely disappeared except interstitial remnants 10 days after abortion. The endometrial regeneration was not fully completed on day 10 after abortion and a few cystically dilated glands were evident. In conclusion, abortion of queens through aglepristone given during mid-gestation is assumed to be the result of damage of uterine venules. This leads to an interstitial haemorrhages and bleeding into the uterine lumen, subsequently resulting in utero-placental detachment.