Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands. SPRMs exert clinically relevant tissue-selective progesterone agonist, antagonist, or mixed agonist/antagonist effects on various progesterone target tissues in vivo. Asoprisnil (J867) is the first SPRM to reach an advanced stage of clinical development for the treatment of symptomatic uterine fibroids and endometriosis. Asoprisnil belongs to the class of 11beta-benzaldoxime-substituted estratrienes that exhibit partial progesterone agonist/antagonist effects with high progesterone receptor specificity in animals and humans. Asoprisnil has no antiglucocorticoid activity in humans at therapeutic doses. It exhibits endometrial antiproliferative effects on the endometrium and breast in primates. Unlike progesterone antagonists, asoprisnil does not induce labor in relevant models of pregnancy and parturition. It induces amenorrhea primarily by targeting the endometrium. In human subjects with uterine fibroids, asoprisnil suppressed both the duration and intensity of uterine bleeding in a dose-dependent manner and reduced tumor volume in the absence of estrogen deprivation. In subjects with endometriosis, asoprisnil was effective in reducing nonmenstrual pain and dysmenorrhea. Asoprisnil may, therefore, provide a novel, tissue-selective approach to control endometriosis-related pain. SPRMs have the potential to become a novel treatment of uterine fibroids and endometriosis.
ObjectiveTo standardize the recording of surgical phenotypic information on endometriosis and related sample collections obtained at laparoscopy, allowing large-scale collaborative research into the condition.DesignAn international collaboration involving 34 clinical/academic centers and three industry collaborators from 16 countries.SettingTwo workshops were conducted in 2013, bringing together 54 clinical, academic, and industry leaders in endometriosis research and management worldwide.Patient(s)None.Intervention(s)A postsurgical scoring sheet containing general and gynecological patient and procedural information, extent of disease, the location and type of endometriotic lesion, and any other findings was developed during several rounds of review. Comments and any systematic surgical data collection tools used in the reviewers' centers were incorporated.Main Outcome Measure(s)The development of a standard recommended (SSF) and minimum required (MSF) form to collect data on the surgical phenotype of endometriosis.Result(s)SSF and MSF include detailed descriptions of lesions, modes of procedures and sample collection, comorbidities, and potential residual disease at the end of surgery, along with previously published instruments such as the revised American Society for Reproductive Medicine and Endometriosis Fertility Index classification tools for comparison and validation.Conclusion(s)This is the first multicenter, international collaboration between academic centers and industry addressing standardization of phenotypic data collection for a specific disease. The Endometriosis Phenome and Biobanking Harmonisation Project SSF and MSF are essential tools to increase our understanding of the pathogenesis of endometriosis by allowing large-scale collaborative research into the condition.
Preterm labour and resultant preterm birth are the most important problems in perinatology. Countless efforts have failed to establish a single effective treatment of preterm labour, partly because the mechanisms regulating the uterus and cervix during pregnancy are not well understood. New knowledge is needed to inhibit early progression of labour (uterine contractility and cervical ripening), and adequate quantitative tools to evaluate the uterus and cervix during pregnancy are lacking. In this review, we outline studies showing that the uterus (myometrium) and cervix pass through a conditioning step in preparation for labour. This step is not easily identifiable with present methods to assess the uterus or cervix. In the uterus, this seemingly irreversible step consists of changes in the electrical properties to make muscle more excitable and responsive to produce forceful contractions. In the cervix, the step consists of softening of the connective tissue components. Progesterone appears to have a dominant role in controlling both the uterus and cervix, as antiprogestins induce early, preterm conditioning leading to preterm labour. Apparently, nitric oxide (NO) also controls conditioning of the uterus and cervix. In the uterus, NO, in concert with progesterone, inhibits uterine contractility. At term, NO production by the uterus and placenta are decreased and allow labour to progress. In contrast, NO in the cervix increases at the end of pregnancy and it may be the final pathway for stimulating cervical ripening by activation of metalloenzymes. The progress of labour can be assessed non-invasively using electromyographic (EMG) signals from the uterus (the driving force for contractility) recorded from the abdominal surface. Uterine EMG bursts detected in this manner characterize uterine contractile events during human and animal pregnancy. A low uterine EMG activity, measured transabdominally throughout most of pregnancy, rises dramatically during labour. EMG activity also increases substantially during preterm labour in humans and rats. This method may be used one day to predict impending preterm labour and identify control steps and treatments. A quantitative method also assesses the cervix, using an optical device which measures collagen fluorescence in the cervix. The collascope estimates cervical collagen content from a fluorescent signal generated when collagen cross-links are illuminated with excitation light of about 340 nm. The system has proved useful in rats and humans at various stages of pregnancy, and indicates that cervical softening occurs progressively in the last one-third of pregnancy. In rats, collascope readings correlate with resistance measurements made in the isolated cervix, which may help to assess cervical function during pregnancy, and indicate control and treatments.
The aim of this study was to determine if nitric oxide (NO) production and nitric oxide synthase (NOS) isoforms change within the uterus and cervix during pregnancy and labour either at term or preterm. NO production was compared in the rat uterus and cervix of non-pregnant and pregnant rats on days 18-22 prior to labour, day 22 during delivery, 1 day post-partum and after treatment with either 10 mg onapristone or progesterone. Uterine NO synthesis, reflected in nitrite production, increased during gestation (194.2 +/- 22.6 nmol/g on day 19) compared with the non-pregnant state (76.2 +/- 18.4 nmol/g, P < 0.05) and decreased during term labour and post-partum. Furthermore, injection of lipopolysaccharide (LPS) (100 micrograms/rat i.p.) on day 20 of gestation resulted in a significant increase in NO synthesis after 6 h. Conversely, cervical NO synthesis and nitrite production was low in the non-pregnant (65.1 +/- 9.2 nmol/g) and pregnant animals on days 18-22 of gestation (53.2 +/- 9.0 nmol/g on day 22, P > 0.05), but markedly increased during term labour (139 +/- 28.6 nmol/g, P < 0.05). Treatment with the antiprogestin onapristone suppressed uterine NO production and increased cervical production while continuous administration of progesterone from day 19 had the opposite effect. LPS produced a significant increase in cervical NO production in both the pregnant (8-fold) and non-pregnant (4-fold) states. All three known NOS isoforms (i.e., iNOS, nNOS and eNOS) were detected in the cervical samples but only two were present in the uterus (iNOs and eNOS). An increase in the presence of iNOS occurred during labour at term compared with cervices collected from day 19. This was contrary to the measurements of the isoform in the uterus. Also, there was a similar increase of nNOS in the cervix during labour. This isoform seemed absent in the uterus during gestation. No significant changes occurred in the abundance of eNOS in the cervix during labour at term compared with day 19. During preterm labour after onapristone, iNOS concentrations increased significantly in the cervix. In order to examine whether the NO pathway plays a role in cervical ripening, the effects of the nitric oxide synthesis inhibitor L-nitro-arginine methylester (L-NAME) on the duration of delivery and on cervical extensibility were also investigated. The duration of delivery was significantly prolonged in L-NAME-treated rats compared with the control group (2.4-fold). Moreover, cervical extensibility decreased significantly (1.7-fold) after in-vitro incubation with L-NAME (P < 0.005). We conclude that the NO system may have an active role in the cascade of processes involved in preparing the uterus and cervix for parturition.
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