Radiosensitization of Breast Cancer Cells with a 2-Methoxyestradiol Analogue Affects DNA Damage and Repair Signaling In Vitro.

Radiation resistance and radiation-related side effects warrant research into alternative strategies in the application of this modality to cancer treatment. Designed in silico to improve the pharmacokinetics and anti-cancer properties of 2-methoxyestradiol, 2-ethyl-3-O-sulfamoyl-estra-1,3,5(10)16-tetraene (ESE-16) disrupts microtubule dynamics and induces apoptosis. Here, we investigated whether pre-exposure of breast cancer cells to low-dose ESE-16 would affect radiation-induced deoxyribonucleic acid (DNA) damage and the consequent repair pathways. MCF-7, MDA-MB-231, and BT-20 cells were exposed to sub-lethal doses of ESE-16 for 24 h before 8 Gy radiation. Flow cytometric quantification of Annexin V, clonogenic studies, micronuclei quantification, assessment of histone H2AX phosphorylation and Ku70 expression were performed to assess cell viability, DNA damage, and repair pathways, in both directly irradiated cells and cells treated with conditioned medium. A small increase in apoptosis was observed as an early consequence, with significant repercussions on long-term cell survival. Overall, a greater degree of DNA damage was detected. Moreover, initiation of the DNA-damage repair response was delayed, with a subsequent sustained elevation. Radiation-induced bystander effects induced similar pathways and were initiated via intercellular signaling. These results justify further investigation of ESE-16 as a radiation-sensitizing agent since pre-exposure appears to augment the response of tumor cells to radiation.

Evaluation of aglepristone and oxytocin on induction of parturition in guinea pig.

BACKGROUND: Induction of parturition in guinea pigs appears to be essential because these animals have a higher rate of reproductive problems than rabbits and small rodents. OBJECTIVES: Since aglepristone (AGL) is a competitive progesterone antagonist acting through binding to progesterone receptors while oxytocin (OT) is a powerful constituent of uterine smooth muscle, the aim of this study was to evaluate the clinical and ultrasonographic impacts of AGL and OT on guinea pig parturition induction. METHODS: In this study, guinea pigs were allocated into five groups; each included five animals on the 61st day of pregnancy. In the aglepristone group (Agle), AGL was administrated subcutaneously (SC) once daily on 2 consecutive days (Days 61 and 62 post mating). Oxytocin (OT) was administered subcutaneously once and twice at 4-h intervals on Day 62 post mating in oxytocin 1 (Oxy1) and oxytocin 2 (Oxy2) groups, respectively. The animals in the aglepristone-oxytocin group (Agle-Oxy) received AGL subcutaneously once daily on 2 consecutive days (Days 61 and 62 post mating) and OT on Day 62 post mating. The remaining sows received saline solution (0.9% NaCl) in the control group. RESULTS: According to the results, fetal heart rate, temperature, neonatal and maternal survival rates were not significantly different between the treatment and control groups (p > 0.05). Biparietal diameter of head and body weight of neonates in the Agle, Oxy2 and Agle-Oxy groups showed a significant decline, compared to the control group (p < 0.05). The time interval between injection and delivery and the duration of pregnancy was significantly reduced in Agle, Oxy2, Agl-Oxy groups, compared to the control and Oxy1 groups. CONCLUSIONS: In conclusion, it seems that treatment Oxy2 can induce parturition in guinea pigs without side effects and lower pain during induction of parturition.

PLCγ1 inhibition combined with inhibition of apoptosis and necroptosis increases cartilage matrix synthesis in IL-1ß-treated rat chondrocytes.

Osteoarthritis (OA) is an age-related, chronic degenerative disease. With the increasing median age of the population, this disease has become an important public health problem. New, disease-modifying therapies are needed. A potential novel molecular target is phospholipase Cγ1 (PLCγ1), a critical enzyme with important functions including calcium signaling regulation and cell proliferation. In rat chondrocytes treated with IL-1ß (20 ng·mL-1 for 36 h), inhibition of PLCγ1 with U73122 (2 µm for 12 h) increased levels and expression of the cartilage matrix components Collagen2 and Aggrecan. This beneficial effect of PLCγ1 inhibition was counteracted by increased chondrocyte apoptosis and necroptosis, increased cell death, and increase levels of ROS, all potentially negative for OA. Combined treatment of IL-1ß + U73122-treated chondrocytes with inhibitors of apoptosis (Z-VAD, 10 µm) and necroptosis (Nec-1, 30 µm) enhanced the increases in levels and expression of Collagen2 and Aggrecan, and prevented the increases in cell death and ROS levels. These results suggest that PLCγ1 inhibition may be a viable approach for an OA therapy, if combined with targeted inhibition of chondrocyte apoptosis and necroptosis.

Progesterone-responsive vaginal leiomyoma and hyperprogesteronemia due to ovarian luteoma in an older bitch.

BACKGROUND: This is the first report about a vaginal leiomyoma concomitant with an ovarian luteoma in a bitch. CASE PRESENTATION: A 11-year-old intact female Labrador retriever was referred because of anuria, constipation and protrusion of a vaginal mass through the vulvar commissure. The bitch had high serum progesterone concentration (4.94 ng/ml). Because of the possibility of progesterone responsiveness causing further increase of the vaginal mass and since the bitch was a poor surgical candidate a 10 mg/kg aglepristone treatment was started SC on referral day 1. A computerized tomography showed a 12.7 × 6.5 × 8.3 cm mass causing urethral and rectal compression, ureteral dilation and hydronephrosis. A vaginal leiomyoma was diagnosed on histology. As serum progesterone concentration kept increasing despite aglepristone treatment, a 0.02 ng/mL twice daily IM alfaprostol treatment was started on day 18. As neither treatment showed remission of clinical signs or luteolysis, ovariohysterectomy was performed on referral day 35. Multiple corpora lutea were found on both ovaries. On histology a luteoma was diagnosed on the left ovary. P4 levels were undetectable 7 days after surgery. Recovery was uneventful and 12 weeks after surgery tomography showed a reduction of 86.7% of the vaginal mass. The bitch has been in good health and able to urinate without any complication ever since. CONCLUSIONS: This case demonstrates the importance of identifying progesterone related conditions as well as the importance of judiciously using a combined medical and surgical approach.

Fertility outcome after medically treated pyometra in dogs.

Cystic endometrial hyperplasia-pyometra complex (CEH/P) is a challenge in canine reproduction. Present study aimed to assess fertility after medical treatment. One-hundred-seventy-four bitches affected by CEH/P received aglepristone on days 1, 2, 8, then every 7 days until blood progesterone < 1.2 ng/mL; cloprostenol was administered on days 3 to 5. Records were grouped according to bodyweight (BW): small (< 10 kg, n = 33), medium (10 ≥ BW < 25 kg, n = 44), large (25 ≥ BW < 40 kg, n = 52), and giant bitches (BW ≥ 40 kg, n = 45). Age; success rate; aglepristone treatments number; relapse, pregnancy rates; diagnosis-relapse, -first, -last litter intervals; litters number after treatment, and LS were analyzed by ANOVA. Overall age was 5.14 ± 1.75 years, without difference among groups. Treatment was 100% successful, without difference in treatments number (4.75 ± 1.18), relapse (15/174, 8.62%) and pregnancy (129/140 litters, 92.14%) rates, intervals diagnosis-relapse (409.63 ± 254.9 days) or -last litter (418.62 ± 129.03 days). The interval diagnosis-first litter was significantly shorter (163.52 ± 51.47 days) and longer (225.17 ± 90.97 days) in small and giant bitches, respectively. Overall, 1.47 ± 0.65 litters were born after treatment. Expected LS was achieved in each group, as shown by ΔLS (actual-expected LS by breed, overall -0.40 ± 1.62) without differences among groups. Concluding, CEH/P affects younger dogs than previously described. Relapses were rarer than previously reported. Medical treatment with aglepristone+cloprostenol is effective and safe, preserving subsequent fertility, as demonstrated by negligible changes in LS.

Safety and efficacy of the selective progesterone receptor modulator asoprisnil for heavy menstrual bleeding with uterine fibroids: pooled analysis of two 12-month, placebo-controlled, randomized trials.

STUDY QUESTION: Can asoprisnil, a selective progesterone receptor modulator, provide clinically meaningful improvements in heavy menstrual bleeding (HMB) associated with uterine fibroids with an acceptable safety profile? SUMMARY ANSWER: Uninterrupted treatment with asoprisnil for 12 months effectively controlled HMB and reduced fibroid and uterine volume with few adverse events. WHAT IS KNOWN ALREADY: In a 3-month study, asoprisnil (5, 10 and 25 mg) suppressed uterine bleeding, reduced fibroid and uterine volume, and improved hematological parameters in a dose-dependent manner. STUDY DESIGN, SIZE, DURATION: In two Phase 3, double-blind, randomized, placebo-controlled, multicentre studies, women received oral asoprisnil 10 mg, asoprisnil 25 mg or placebo (2:2:1) once daily for up to 12 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal women ≥18 years of age in North America with HMB associated with uterine fibroids were included (N = 907). The primary efficacy endpoint was the percentage of women who met all three predefined criteria at 12 months or the final month for patients who prematurely discontinued: (1) ≥50% reduction in monthly blood loss (MBL) by menstrual pictogram, (2) hemoglobin concentration ≥11 g/dL or an increase of ≥1 g/dL, and (3) no interventional therapy for uterine fibroids. Secondary efficacy endpoints included changes in other menstrual bleeding parameters, volume of the largest fibroids, uterine volume and health-related quality of life (HRQL). MAIN RESULTS AND THE ROLE OF CHANCE: In all, 90% and 93% of women in the asoprisnil 10-mg and 25-mg groups, respectively, and 35% of women in the placebo group met the primary endpoint (P < 0.001). Similar results were observed at month 6 (P < 0.001). The percentage of women who achieved amenorrhea in any specified month ranged from 66-78% in the asoprisnil 10-mg group and 83-93% in the asoprisnil 25-mg group, significantly higher than with placebo (3-12%, P < 0.001). Hemoglobin increased rapidly (by month 2) with asoprisnil treatment and was significantly higher versus placebo throughout treatment. The primary fibroid and uterine volumes were significantly reduced from baseline through month 12 with asoprisnil 10 mg (median changes up to -48% and -28%, respectively) and 25 mg (median changes up to -63% and -39%, respectively) versus placebo (median changes up to +16% and +13%, respectively; all P < 0.001). Dose-dependent, significant improvements in HRQL (Uterine Fibroid Symptom and Quality of Life instrument) were observed with asoprisnil treatment. Asoprisnil was generally well tolerated. Endometrial biopsies indicated dose- and time-dependent decreases in proliferative patterns and increases in quiescent or minimally stimulated endometrium at month 12 of treatment. Although not statistically significantly different at month 6, mean endometrial thickness at month 12 increased by ~2 mm in both asoprisnil groups compared with placebo (P < 0.01). This effect was associated with cystic changes in the endometrium on MRI and ultrasonography, which led to invasive diagnostic and therapeutic procedures in some asoprisnil-treated women. LIMITATIONS, REASONS FOR CAUTION: Most study participants were black; few Asian and Hispanic women participated. The study duration may have been insufficient to fully characterize the endometrial effects. WIDER IMPLICATIONS OF THE FINDINGS: Daily uninterrupted treatment with asoprisnil was highly effective in controlling menstrual bleeding, improving anemia, reducing fibroid and uterine volume, and increasing HRQL in women with HMB associated with uterine fibroids. However, this treatment led to an increase in endometrial thickness and invasive diagnostic and therapeutic procedures, with potential unknown consequences. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by AbbVie Inc. (prior sponsors: TAP Pharmaceutical Products Inc., Abbott Laboratories). E.A. Stewart was a site investigator in the Phase 2 study of asoprisnil and consulted for TAP during the design and conduct of these studies while at Harvard Medical School and Brigham and Women's Hospital. She received support from National Institutes of Health grants HD063312, HS023418 and HD074711 and research funding, paid to Mayo Clinic for patient care costs related to an NIH-funded trial from InSightec Ltd. She consulted for AbbVie, Allergan, Bayer HealthCare AG, Gynesonics, and Welltwigs. She received royalties from UpToDate and the Med Learning Group. M.P. Diamond received research funding for the conduct of the studies paid to the institution and consulted for AbbVie. He is a stockholder and board and director member of Advanced Reproductive Care. He has also received funding for study conduct paid to the institution from Bayer and ObsEva. A.R.W. Williams consulted for TAP and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr consulted for and received research funding from AbbVie. E.R. Myers consulted for AbbVie, Allergan and Bayer. R.A. Feldman received compensation for serving as a principal investigator and participating in the conduct of the trial. W. Elger was co-inventor of several patents related to asoprisnil. C. Mattia-Goldberg is a former employee of AbbVie and may own AbbVie stock or stock options. B.M. Schwefel and K. Chwalisz are employees of AbbVie and may own AbbVie stock or stock options. TRIAL REGISTRATION NUMBER: NCT00152269, NCT00160381 (clinicaltrials.gov). TRIAL REGISTRATION DATE: 7 September 2005; 8 September 2005. DATE OF FIRST PATIENT'S ENROLMENT: 12 September 2002; 6 September 2002.

Effect of oral misoprostol, alone or in combination with aglepristone, on mid-term pregnancy termination in cats.

OBJECTIVES: This study aimed to determine the efficacy and safety of oral misoprostol (MIS) administration in the induction of mid-term pregnancy termination in cats. METHODS: Twenty-eight cats that were pregnant for 30-40 days were allocated to four groups. The aglepristone (AGL) group (n = 7) received 10 mg/kg SC aglepristone q24h for two consecutive days. In the AGL+MIS group (n = 7), AGL (as administered in the AGL group) and MIS (200 µg/cat PO q12h until the start of abortion) were administered. The MIS200 (n = 7) and MIS400 groups (n = 7) received MIS (200 or 400 µg/cat misoprostol, respectively) alone PO q12h until the start of abortion. Blood samples were collected at the start of treatment (d0), 4 days after the start of treatment (d4) and on the day of complete abortion/end of administration (dA/d7). RESULTS: The efficacy of the treatment was 71.4% in the AGL group, 100% in the AGL+MIS group, 0% in MIS200 group and 57.4% in MIS400 group (P = 0.004). No significance was found in relation to the interval from treatment to the start/end of abortion and the duration of abortion in all groups. The most observed side effect was vomiting in both groups administered MIS, particularly in the MIS400 group (56.7%). Progesterone (P4) concentrations were reduced during the abortion, but not to basal levels, in all groups. P4 concentrations were significantly lower at dA/d7 in the MIS400 group compared with the AGL and AGL+MIS groups (P = 0.002). CONCLUSIONS AND RELEVANCE: The results obtained from this study showed that low doses of MIS do not induce abortions in cats but increase the effect of AGL. Although higher doses could terminate pregnancies, this also causes intense unwanted side effects. Therefore, the use of MIS alone as an abortifacient in cats is not recommended. For mid-term pregnancy termination in cats, the combination of misoprostol and aglepristone provides a more effective abortifacient than using either of them alone.

Neonatal puppy survival after planned caesarean section in the bitch using aglepristone as a primer: A retrospective study on 74 cases.

Since most of dystocia end up in caesarean sections (C-sections), the history of any problem during whelping is a good reason to plan in advance a further C-section. Our aim was to confirm that on a large sample and over an extended period of time, mortality in puppies <2 weeks of age was low, born after a planned C-section using aglepristone as a primer. Seventy-four C-sections on 59 different bitches were included. Bitches were monitored during oestrus to estimate the day of ovulation by progesterone assays; 60, 61 or 62 days after ovulation, foetal viability was checked by ultrasonography and progesterone plasma level was measured. None of the bitches was at term (progesterone plasma level >2 ng/ml). An injection of aglepristone was performed in late afternoon to block the effect of progesterone, mimicking its drop at the end of pregnancy. The C-section was conducted the following morning. Twenty-one breeds were represented most of which were bulldogs (26%, 21/74) and Great Danes (16%, 13/74). Four hundred and thirty-five puppies were born. A total of 43/435 puppies died within the first 2 weeks (9.89%). None of the puppies showed any external signs of prematurity. The average number of deaths per litter relative to the date after ovulation was similar (0.5 pups per litter at day 60, 0.7 at day 61, 0.4 at day 62). This study shows that planned C-section after an accurate determination of ovulation and using aglepristone as a primer is a safe procedure for bitches and their offspring. It may be offered to owners if a pregnant bitch is "at risk" of dystocia.

Discovery of Vilaprisan (BAY 1002670): A Highly Potent and Selective Progesterone Receptor Modulator Optimized for Gynecologic Therapies.

Progesterone plays an important role in the female reproductive system. However, there is also evidence that gynecologic disorders/diseases such as uterine fibroids and endometriosis are progesterone-dependent. Steroidal and non-steroidal selective progesterone receptor modulators (SPRMs) have shown potential for the treatment of such diseases. Steroidal SPRMs, including mifepristone and ulipristal acetate, have proven effective in clinical trials. However, several steroidal SPRMs containing a dimethylamino substituent have been associated with elevated liver enzymes in patients. An earlier drug discovery program identified lonaprisan as a highly selective SPRM that did not show drug-related change in liver enzyme activity. Building on data obtained from that work, here we describe the research program that culminated in the discovery of a novel steroidal SPRM, vilaprisan, which combines an extremely high potency with very favorable drug metabolism and pharmacokinetic properties. Vilaprisan has entered clinical development and is currently undergoing phase 3 clinical trials.

Evaluation of an alternative treatment protocol by aglepristone to induce parturition in ewes with an experimental model of early pregnancy toxemia.

A new protocol with aglepristone to induce parturition in ewes with pregnancy toxemia has been reported in the present manuscript. Four experimental groups were defined: Group AG5 (n = 10), Group DEX (n = 10), Group NC (n = 5) and Group PT (n = 5) in which ewes were injected twice with 10 mg/kg of aglepristone and 5 ml dexamethasone in first two groups, respectively; whereas negative control and pregnancy toxemia groups received no treatment for parturition induction. Different clinical parameters associated with parturition in ewes and their newborns were investigated. Blood hematology and biochemical measurements were carried out both in ewes and lambs. Blood pH values of lambs were recorded during the study. The injection time-lambing time, injection time-vaginal discharge intervals, placental expulsion periods, placental weight and vaginal delivery interval between lambs, hematological and biochemical results were not statistically different among the groups (p > 0,05). Increased NEFA and ß-HBA concentrations accompanied the disease and all ewes in AG, DEX and PT Groups developed clinical pregnancy toxemia (NEFA; P = 0,009) and ß-HBA; (P = 0,039). The differences in rectal body temperature of lambs were not significant (p > 0,05), whereas birth weight was found statistically significant among groups (p < 0,05). Blood pH, biochemical and hematologic measurements of lambs had also significant differences depending on different time points. Parturition pathology by means of incomplete cervical dilatation was severely observed in DEX Group. The results of this study show that aglepristone application in pregnancy toxemia to induce parturition could precisely control lambing time without any side effects in either mothers or lambs. Apart from these, it could be speculated that dexamethasone seems to induce parturition causing crucial pathologies, which results in important and risky changes in newborns' life. Incomplete cervical dilatation and continued ineffective uterine contractions could be a major factor of newborn losses because of placental separation and cessation of blood supply.

The in vitro effects of a novel estradiol analog on cell proliferation and morphology in human epithelial cervical carcinoma.

BACKGROUND: The majority of novel chemotherapeutics target the cell cycle, aiming to effect arrest and cause apoptosis. One such agent, 2-methoxyestradiol (2ME), has been shown to possess anticancer properties against numerous cancer types, both in vitro and in vivo. Despite its promise, 2ME has exhibited limitations, including low oral bioavailability and rapid hepatic enzymatic inactivation in vivo. A novel sulphamoylated estrogen analog, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16), was in silico-designed in our laboratory to overcome these issues. It was then synthesized by a pharmaceutical company and used in an in vitro antiproliferative effect study on a human cervical carcinoma (HeLa) cell line. RESULTS: Cell proliferation data obtained from the crystal violet assay and real-time cell analysis demonstrated that 0.2 µM of ESE-16 had a significant inhibitory effect on the HeLa cells 24 h post-exposure. Immunofluorescence showed that ESE-16 is a microtubule disruptor that causes cells to undergo a mitotic block. Qualitative morphological studies using polarization-optical transmitted light differential interference contrast (PlasDIC) and light microscopy revealed a decrease in cell density and an increase in the number of cells arrested in metaphase. After ESE-16 exposure, hallmarks of apoptosis were also observed, including membrane blebbing, chromatin condensation and the presence of apoptotic bodies. Flow cytometry provided quantitative results from cell cycle progression analysis, indicating cells undergoing apoptosis and cells in the G2/M phase of the cell cycle, confirming cell cycle arrest in metaphase after ESE-16 treatment. Quantification of the ESE-16-mediated upregulation of cyclin B in HeLa cells and spectrophotometric and flow cytometric confirmation of cell death via apoptosis further confirmed the substance's impact. CONCLUSION: ESE-16 exerts its antiproliferative effects through microtubule disruption, which induces a mitotic block culminating in apoptosis. This research provided information on ESE-16 as a potential antitumor agent and on cellular targets that could aid in the design of prospective microtubule-disrupting compounds. Further in vitro and in vivo investigations of this novel compound are needed.

The past, present, and future of selective progesterone receptor modulators in the management of uterine fibroids.

Uterine fibroids are common in women of reproductive age and can have a significant impact on quality of life and fertility. Although a number of international obstetrics/gynecology societies have issued evidence-based clinical practice guidelines for the management of symptomatic uterine fibroids, many of these guidelines do not yet reflect the most recent clinical evidence and approved indication for one of the key medical management options: the selective progesterone receptor modulator class. This article aims to share the clinical experience gained with selective progesterone receptor modulators in Europe and Canada by reviewing the historical development of selective progesterone receptor modulators, current best practices for selective progesterone receptor modulator use based on available data, and potential future uses for selective progesterone receptor modulators in uterine fibroids and other gynecologic conditions.

Progesterone receptor modulators for endometriosis.

BACKGROUND: Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterine cavity. This condition is oestrogen-dependent and thus is seen primarily during the reproductive years. Owing to their antiproliferative effects in the endometrium, progesterone receptor modulators (PRMs) have been advocated for treatment of endometriosis. OBJECTIVES: To assess the effectiveness and safety of PRMs primarily in terms of pain relief as compared with other treatments or placebo or no treatment in women of reproductive age with endometriosis. SEARCH METHODS: We searched the following electronic databases, trial registers, and websites: the Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register of Controlled Trials, the Central Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, clinicaltrials.gov, and the World Health Organization (WHO) platform, from inception to 28 November 2016. We handsearched reference lists of articles retrieved by the search. SELECTION CRITERIA: We included randomised controlled trials (RCTs) published in all languages that examined effects of PRMs for treatment of symptomatic endometriosis. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by the Cochrane Collaboration. Primary outcomes included measures of pain and side effects. MAIN RESULTS: We included 10 randomised controlled trials (RCTs) with 960 women. Two RCTs compared mifepristone versus placebo or versus a different dose of mifepristone, one RCT compared asoprisnil versus placebo, one compared ulipristal versus leuprolide acetate, and four compared gestrinone versus danazol, gonadotropin-releasing hormone (GnRH) analogues, or a different dose of gestrinone. The quality of evidence ranged from high to very low. The main limitations were serious risk of bias (associated with poor reporting of methods and high or unclear rates of attrition in most studies), very serious imprecision (associated with low event rates and wide confidence intervals), and indirectness (outcome assessed in a select subgroup of participants). Mifepristone versus placebo One study made this comparison and reported rates of painful symptoms among women who reported symptoms at baseline.At three months, the mifepristone group had lower rates of dysmenorrhoea (odds ratio (OR) 0.08, 95% confidence interval (CI) 0.04 to 0.17; one RCT, n =352; moderate-quality evidence), suggesting that if 40% of women taking placebo experience dysmenorrhoea, then between 3% and 10% of women taking mifepristone will do so. The mifepristone group also had lower rates of dyspareunia (OR 0.23, 95% CI 0.11 to 0.51; one RCT, n = 223; low-quality evidence). However, the mifepristone group had higher rates of side effects: Nearly 90% had amenorrhoea and 24% had hot flushes, although the placebo group reported only one event of each (1%) (high-quality evidence). Evidence was insufficient to show differences in rates of nausea, vomiting, or fatigue, if present. Mifepristone dose comparisons Two studies compared doses of mifepristone and found insufficient evidence to show differences between different doses in terms of effectiveness or safety, if present. However, subgroup analysis of comparisons between mifepristone and placebo suggest that the 2.5 mg dose may be less effective than 5 mg or 10 mg for treating dysmenorrhoea or dyspareunia. Gestrinone comparisons Ons study compared gestrinone with danazol, and another study compared gestrinone with leuprolin.Evidence was insufficient to show differences, if present, between gestrinone and danazol in rate of pain relief (those reporting no or mild pelvic pain) (OR 0.71, 95% CI 0.33 to 1.56; two RCTs, n = 230; very low-quality evidence), dysmenorrhoea (OR 0.72, 95% CI 0.39 to 1.33; two RCTs, n = 214; very low-quality evidence), or dyspareunia (OR 0.83, 95% CI 0.37 to 1.86; two RCTs, n = 222; very low-quality evidence). The gestrinone group had a higher rate of hirsutism (OR 2.63, 95% CI 1.60 to 4.32; two RCTs, n = 302; very low-quality evidence) and a lower rate of decreased breast size (OR 0.62, 95% CI 0.38 to 0.98; two RCTs, n = 302; low-quality evidence). Evidence was insufficient to show differences between groups, if present, in rate of hot flushes (OR 0.79, 95% CI 0.50 to 1.26; two RCTs, n = 302; very low-quality evidence) or acne (OR 1.45, 95% CI 0.90 to 2.33; two RCTs, n = 302; low-quality evidence).When researchers compared gestrinone versus leuprolin through measurements on the 1 to 3 verbal rating scale (lower score denotes benefit), the mean dysmenorrhoea score was higher in the gestrinone group (MD 0.35 points, 95% CI 0.12 to 0.58; one RCT, n = 55; low-quality evidence), but the mean dyspareunia score was lower in this group (MD 0.33 points, 95% CI 0.62 to 0.04; low-quality evidence). The gestrinone group had lower rates of amenorrhoea (OR 0.04, 95% CI 0.01 to 0.38; one RCT, n = 49; low-quality evidence) and hot flushes (OR 0.20, 95% CI 0.06 to 0.63; one study, n = 55; low quality evidence) but higher rates of spotting or bleeding (OR 22.92, 95% CI 2.64 to 198.66; one RCT, n = 49; low-quality evidence).Evidence was insufficient to show differences in effectiveness or safety between different doses of gestrinone, if present. Asoprisnil versus placebo One study (n = 130) made this comparison but did not report data suitable for analysis. Ulipristal versus leuprolide acetate One study (n = 38) made this comparison but did not report data suitable for analysis. AUTHORS' CONCLUSIONS: Among women with endometriosis, moderate-quality evidence shows that mifepristone relieves dysmenorrhoea, and low-quality evidence suggests that this agent relieves dyspareunia, although amenorrhoea and hot flushes are common side effects. Data on dosage were inconclusive, although they suggest that the 2.5 mg dose of mifepristone may be less effective than higher doses. We found insufficient evidence to permit firm conclusions about the safety and effectiveness of other progesterone receptor modulators.

Selective progesterone receptor modulators (SPRMs) for uterine fibroids.

BACKGROUND: Uterine fibroids are smooth muscle tumours arising from the uterus. These tumours, although benign, are commonly associated with abnormal uterine bleeding, bulk symptoms and reproductive dysfunction. The importance of progesterone in fibroid pathogenesis supports selective progesterone receptor modulators (SPRMs) as effective treatment. Both biochemical and clinical evidence suggests that SPRMs may reduce fibroid growth and ameliorate symptoms. SPRMs can cause unique histological changes to the endometrium that are not related to cancer, are not precancerous and have been found to be benign and reversible. This review summarises randomised trials conducted to evaluate the effectiveness of SPRMs as a class of medication for treatment of individuals with fibroids. OBJECTIVES: To evaluate the effectiveness and safety of SPRMs for treatment of premenopausal women with uterine fibroids. SEARCH METHODS: We searched the Specialised Register of the Cochrane Gynaecology and Fertility Group, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and clinical trials registries from database inception to May 2016. We handsearched the reference lists of relevant articles and contacted experts in the field to request additional data. SELECTION CRITERIA: Included studies were randomised controlled trials (RCTs) of premenopausal women with fibroids who were treated for at least three months with a SPRM. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed all eligible studies identified by the search. We extracted data and assessed risk of bias independently using standard forms. We analysed data using mean differences (MDs) or standardised mean differences (SMDs) for continuous data and odds ratios (ORs) for dichotomous data. We performed meta-analyses using the random-effects model. Our primary outcome was change in fibroid-related symptoms. MAIN RESULTS: We included in the review 14 RCTs with a total of 1215 study participants. We could not extract complete data from three studies. We included in the meta-analysis 11 studies involving 1021 study participants: 685 received SPRMs and 336 were given a control intervention (placebo or leuprolide). Investigators evaluated three SPRMs: mifepristone (five studies), ulipristal acetate (four studies) and asoprisnil (two studies). The primary outcome was change in fibroid-related symptoms (symptom severity, health-related quality of life, abnormal uterine bleeding, pelvic pain). Adverse event reporting in the included studies was limited to SPRM-associated endometrial changes. More than half (8/14) of these studies were at low risk of bias in all domains. The most common limitation of the other studies was poor reporting of methods. The main limitation for the overall quality of evidence was potential publication bias. SPRM versus placebo SPRM treatment resulted in improvements in fibroid symptom severity (MD -20.04 points, 95% confidence interval (CI) -26.63 to -13.46; four RCTs, 171 women, I2 = 0%; moderate-quality evidence) and health-related quality of life (MD 22.52 points, 95% CI 12.87 to 32.17; four RCTs, 200 women, I2 = 63%; moderate-quality evidence) on the Uterine Fibroid Symptom Quality of Life Scale (UFS-QoL, scale 0 to 100). Women treated with an SPRM showed reduced menstrual blood loss on patient-reported bleeding scales, although this effect was small (SMD -1.11, 95% CI -1.38 to -0.83; three RCTs, 310 women, I2 = 0%; moderate-quality evidence), along with higher rates of amenorrhoea (29 per 1000 in the placebo group vs 237 to 961 per 1000 in the SPRM group; OR 82.50, 95% CI 37.01 to 183.90; seven RCTs, 590 women, I2 = 0%; moderate-quality evidence), compared with those given placebo. We could draw no conclusions regarding changes in pelvic pain owing to variability in the estimates. With respect to adverse effects, SPRM-associated endometrial changes were more common after SPRM therapy than after placebo (OR 15.12, 95% CI 6.45 to 35.47; five RCTs, 405 women, I2 = 0%; low-quality evidence). SPRM versus leuprolide acetate In comparing SPRM versus other treatments, two RCTs evaluated SPRM versus leuprolide acetate. One RCT reported primary outcomes. No evidence suggested a difference between SPRM and leuprolide groups for improvement in quality of life, as measured by UFS-QoL fibroid symptom severity scores (MD -3.70 points, 95% CI -9.85 to 2.45; one RCT, 281 women; moderate-quality evidence) and health-related quality of life scores (MD 1.06 points, 95% CI -5.73 to 7.85; one RCT, 281 women; moderate-quality evidence). It was unclear whether results showed a difference between SPRM and leuprolide groups for reduction in menstrual blood loss based on the pictorial blood loss assessment chart (PBAC), as confidence intervals were wide (MD 6 points, 95% CI -40.95 to 50.95; one RCT, 281 women; low-quality evidence), or for rates of amenorrhoea (804 per 1000 in the placebo group vs 732 to 933 per 1000 in the SPRM group; OR 1.14, 95% CI 0.60 to 2.16; one RCT, 280 women; moderate-quality evidence). No evidence revealed differences between groups in pelvic pain scores based on the McGill Pain Questionnaire (scale 0 to 45) (MD -0.01 points, 95% CI -2.14 to 2.12; 281 women; moderate-quality evidence). With respect to adverse effects, SPRM-associated endometrial changes were more common after SPRM therapy than after leuprolide treatment (OR 10.45, 95% CI 5.38 to 20.33; 301 women; moderate-quality evidence). AUTHORS' CONCLUSIONS: Short-term use of SPRMs resulted in improved quality of life, reduced menstrual bleeding and higher rates of amenorrhoea than were seen with placebo. Thus, SPRMs may provide effective treatment for women with symptomatic fibroids. Evidence derived from one RCT showed no difference between leuprolide acetate and SPRM with respect to improved quality of life and bleeding symptoms. Evidence was insufficient to show whether effectiveness was different between SPRMs and leuprolide. Investigators more frequently observed SPRM-associated endometrial changes in women treated with SPRMs than in those treated with placebo or leuprolide acetate. As noted above, SPRM-associated endometrial changes are benign, are not related to cancer and are not precancerous. Reporting bias may impact the conclusion of this meta-analysis. Well-designed RCTs comparing SPRMs versus other treatments are needed.

Prognostic impact of neoadjuvant aglepristone treatment in clinicopathological parameters of progesterone receptor-positive canine mammary carcinomas.

Neoadjuvant treatment of canine mammary carcinomas with the progesterone receptor (PR) antagonist aglepristone has a PR expression-related inhibiting effect on proliferation index (PI). The aim of this study was to evaluate the effect of the treatment in the disease-free period (DFP) and overall survival (OS) of canine mammary carcinomas. Fifty female dogs with mammary carcinomas were treated with aglepristone (n = 34) or oil vehicle (n = 16) before surgery (day 15). PR expression and PI were analysed by immunohistochemistry in samples taken at days 1 and 15. Epidemiological and clinicopathological data were assessed. DFP and OS data were retrieved every 4-6 months for at least 24 months after surgery. Aglepristone treatment increased DFP of animals bearing PR+ tumours with size smaller than 3 cm, complex and mixed tumours, with histologic grades I and II, and with PI ≤ 10%. Although further studies are necessary, current evidence points to treatment with aglepristone as useful for the management of canine mammary tumours.

An Evidence-based Approach to the Medical Management of Fibroids: A Systematic Review.

Fibroids are the most common tumor of the female reproductive tract, but approved medical treatments are limited. Patients demand uterine-sparing treatments which preserve fertility and avoid surgery. We systematically reviewed PubMed and Cochrane databases from January 1985 to November 2015 for evidence-based medical therapies for fibroids in the context of disease prevention, treatment of early disease, treatment of symptomatic disease, and preoperative management. We identified 2182 studies, of which 52 studies met inclusion and exclusion criteria. Published data affirm the efficacy of multiple agents, which are promising avenues for the development of medical alternatives to surgery.

Role of Medical Management for Uterine Leiomyomas.

Uterine leiomyomas, or fibroids, are the most common benign tumor in reproductive aged women. Affected women may remain asymptomatic or may report symptoms related to abnormal uterine bleeding, infertility, or pelvic pain and pressure. Depending on a patient's symptomatology and reproductive plans, treatment options include expectant management, medical management (hormonal and non-hormonal), or surgical management (myomectomy or hysterectomy). In those wishing to defer surgical management, non-hormonal therapies such as non-steroidal anti-inflammatory drugs and tranexamic acid have been shown to decrease menstrual blood loss. In patients with more symptomatic leiomyomas, hormonal therapies such as gonadotropin-releasing hormone agonists and selective progesterone receptor modulators are effective at reducing leiomyoma volume, uterine size, and menstrual blood loss. This manuscript will detail the available and emerging hormonal and non-hormonal treatments for symptomatic uterine leiomyomas.

Progesterone receptor isoform A may regulate the effects of neoadjuvant aglepristone in canine mammary carcinoma.

BACKGROUND: Progesterone receptors play a key role in the development of canine mammary tumours, and recent research has focussed on their possible value as therapeutic targets using antiprogestins. Cloning and sequencing of the progesterone receptor gene has shown that the receptor has two isoforms, A and B, transcribed from a single gene. Experimental studies in human breast cancer suggest that the differential expression of progesterone receptor isoforms has implications for hormone therapy responsiveness. This study examined the effects of the antiprogestin aglepristone on cell proliferation and mRNA expression of progesterone receptor isoforms A and B in mammary carcinomas in dogs treated with 20 mg/Kg of aglepristone (n = 22) or vehicle (n = 5) twice before surgery. RESULTS: Formalin-fixed, paraffin-embedded tissue samples taken before and after treatment were used to analyse total progesterone receptor and both isoforms by RT-qPCR and Ki67 antigen labelling. Both total progesterone receptor and isoform A mRNA expression levels decreased after treatment with aglepristone. Furthermore, a significant decrease in the proliferation index (percentage of Ki67-labelled cells) was observed in progesterone-receptor positive and isoform-A positive tumours in aglepristone-treated dogs. CONCLUSIONS: These findings suggest that the antiproliferative effects of aglepristone in canine mammary carcinomas are mediated by progesterone receptor isoform A.

A retrospective study of bitches with pyometra, medically treated with aglepristone.

Pyometra is a common and life-threatening disease of intact bitches caused by hormonal influence of the uterus in combination with bacterial infection. The treatment of choice is ovariohysterectomy, but several purely medical options are available. Common drugs used for medical treatment in combination with antimicrobials are progesterone receptor blockers, prostaglandins, and dopamine agonists. The aim of this study was to evaluate long-term recovery and fertility after treatment with the progesterone receptor blocker aglepristone in bitches with pyometra. Data from 28 bitches with pyometra, admitted to the University Animal Hospital, Swedish University of Agricultural Sciences, during a 9-year period, were studied retrospectively and followed up by telephone interviews with the owners. The bitches had been treated with aglepristone at a dose of 10 mg/kg on a median of four occasions. All bitches had also been treated with antimicrobial drugs for a mean duration of 23 days, the most frequently used being enrofloxacin. Escherichia coli were the most commonly isolated bacteria from cranial vagina. The outcome was assessed for up to 6 years after treatment. The success rate, determined as restored clinically healthy status, was 75% (21/28 bitches), and the recurrence rate of disease was 48% (10/21 bitches). The mean time until recurrence was 10.5 months after the end of treatment. After treatment, 69% (9/13) of the mated bitches produced puppies. Of the seven bitches that did not have a successful treatment, six were ovariohysterectomized and one was euthanized. In conclusion, medical treatment with aglepristone in combination with antimicrobial therapy was successful in 75% of the bitches studied and the recurrence rate was 48%.

Medical treatment for pyometra in dogs.

Pyometra is a reproductive disorder very common in bitches over 8 years of age in which physiological effects of progesterone on the uterus play a major role. The traditional therapy for pyometra is ovariohysterectomy. The main advantage of ovariohysterectomy over medical management is that it is both curative and preventive for recurrence of pyometra. However, surgery is associated with the risk of anaesthesia and renders the bitch sterile. During the last 10 years, numerous medical treatments have been proposed to treat both open and closed cervix pyometra. The most effective medical treatment with minor side effects seems to be the repeated administration of aglepristone with or without the additional treatment with low doses of prostaglandins.