SciCombinator

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Concept: Selective progesterone receptor modulator

28

The majority of symptomatic uterine fibroids are currently treated by surgical interventions (myomectomy or hysterectomy) or radiological treatments (uterine artery embolisation or focussed ultrasound surgery). None of these treatments is a panacea, and what is conspicuous is the lack of an effective long-term medical therapy for a disorder so common among women of reproductive age. It has been known for some time that progesterone and its receptors enhance proliferative activity in fibroids and this has raised the possibility that anti-progestins and (PRMs) could be useful in the medical management of fibroids. Some of the compounds which have produced promising results in recent clinical trials or research studies include mifepristone, CDB-4124 (telapristone), CP-8947, J-867 (asoprisnil) and CDB-2914 (ulipristal acetate or UA). UA has recently completed Phase III clinical trials with very encouraging results, and has now acquired a licence for clinical use in Europe. While considerable research has yet to be done on the long-term safety and efficacy of UA there is nevertheless good reason for optimism on the emergence of effective medical therapy in the form of UA and possibly other PRMs.

Concepts: Myomectomy, Uterine artery embolization, Clinical trial, Medicine, Uterus, Hysterectomy, Selective progesterone receptor modulator, Uterine fibroids

25

Several studies suggest that resistance to progesterone may contribute to the pathophysiology of endometriosis. Progesterone mediates its biological activity via the 2 progesterone receptor (PR) isoforms (PR-A and PR-B). Effects of progesterone are determined by the PR-A:PR-B ratio such that a PR-B-dominant state promotes progesterone signaling, whereas a PR-A-dominant state decreases progesterone responsiveness. Our objective was to compare the abundance and cellular localization of the PR isoforms in endometrium and endometriotic lesions from women with and without peritoneal and ovarian endometriosis.

Concepts: Selective progesterone receptor modulator, Corpus luteum, Menstrual cycle, Endometrium, Progesterone, Estrogen, Endometriosis

24

The progesterone receptor plays an essential role in uterine physiology and reproduction. Selective progesterone receptor modulators (SPRMs) have emerged as a valuable treatment option for hormone dependent conditions like uterine fibroids, which have a major impact on women’s quality of life. SPRMs offer potential for longer term medical treatment and thereby patients may avoid surgical intervention. Areas covered: The authors have reviewed the functional role of the progesterone receptor and its isoforms and their molecular mechanisms of action via genomic and non-genomic pathways. The current knowledge of the interaction of the PR and different SPRMs tested in clinical trials has been reviewed. The authors focused on pharmacological effects of selected SPRMs on the endometrium, their anti-proliferative action, and their suppression of bleeding. Potential underlying molecular mechanisms and the specific histological changes in the endometrium induced by SPRMs (PAEC; Progesterone receptor modulator Associated Endometrial Changes) have been discussed. The clinical potential of this compound class including its impact on quality of life has been covered. Expert Opinion: Clinical studies indicate SPRMs hold promise for treatment of benign gynecological complaints (fibroids, heavy menstrual bleeding; HMB). There however remains a knowledge gap concerning mechanism of action.

Concepts: Pregnancy, Uterus, Gynecology, Selective progesterone receptor modulator, Menstrual cycle, Pharmacology, Progesterone, Endometrium

23

Selective progesterone receptor modulators have shown efficacy in the treatment of endometriosis, however they are not currently licensed in Canada for this purpose. Their histomorphological effects have been well documented in the endometrium, but not in endometriosis.

Concepts: Menstrual cycle, Endometrium, Progesterone receptor, Endometriosis, Progesterone, Selective progesterone receptor modulator

3

Uterine fibroids are the commonest benign tumours of women and affect all races with a cumulative lifetime risk of around 70%. Despite their high prevalence and the heavy economic burden of treatment, fibroids have received remarkably little attention compared to common female malignant tumours. This article reviews recent progress in understanding the biological nature of fibroids, their life cycle and their molecular genetic origins. Recent progress in surgical and interventional management is briefly reviewed, and medical management options, including treatment with selective progesterone receptor modulators, are also discussed.

Concepts: Oncology, Selective progesterone receptor modulator

1

To assess efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas.

Concepts: Leiomyoma, Ulipristal acetate, Pharmacology, Progesterone receptor, Hormonal contraception, Progesterone, Selective progesterone receptor modulator, Randomized controlled trial

0

Current medical treatments for endometriosis are very limited. Progestin and selective progesterone receptor modulators (SPRM) are developed but their efficacy, safety, mechanism and recurrence in endometriosis are not fully studied.

Concepts: Hormonal contraception, Combined oral contraceptive pill, Progesterone receptor, Progestin, Estrogen, Progesterone, Selective progesterone receptor modulator

0

Progesterone receptor (PGR) and ARID1A have important roles in the establishment and maintenance of pregnancy in the uterus. In present studies, we examined the expression of mitochondrial tumor suppressor 1 (MTUS1) in the murine uterus during early pregnancy as well as in response to ovarian steroid hormone treatment.

Concepts: Nuclear receptor, Selective progesterone receptor modulator, Pregnancy, Metabolism, Estrogen, Hormone, Steroid, Progesterone

0

Ulipristal acetate (UPA) is a selective progesterone receptor modulator, which has been used to treat uterine fibroids. Many published reports about the outcomes indicate effective control of bleeding and reduction in the fibroid volume following both short- and long-term therapy. However, the reported volume reduction varies across different reports. Therefore, the purpose of this study was to investigate the factors that can affect the volume reduction of uterine fibroids, after short-term UPA therapy in patients with symptomatic uterine fibroids.

Concepts: Uterine fibroids, Selective progesterone receptor modulator

0

Vast numbers of xenobiotics are known still to be present in treated municipal wastewater treatment plant (WWTP) effluents. Some of these possess endocrine-disrupting potency and pose risks for exposed aquatic animals. We searched for 17 potential environmental contaminants having affinity to the progesterone receptor. Relative potency values of these progesterone receptor-active chemicals were obtained. On the basis of relative potencies and measured environmental concentrations, the contribution of progestins to measured progestagenic activities was evaluated. Wastewaters (influent and effluent) and surrounding surface waters (upstream and downstream) at six municipal WWTPs were screened using instrumental chemical analysis and in vitro reporter gene bioassay. We showed the presence of target compounds and (anti-)progestagenic activities in municipal wastewater and surface water. Nine and seven progestins were identified in influent and effluent wastewaters, respectively. Only two compounds, progesterone and medroxyprogesterone were found in surface waters. Progestagenic agonistic activities in influents were partially masked by strong anti-progestagenic activities that were detected in all influents and ranged from 2.63 to 83 ng/L of mifepristone equivalents (EQs). Progestagenic activities were detected in all effluents and ranged from 0.06 to 0.47 ng/L of reference compound ORG 2058 EQs (a synthetic progestin equivalents), thus indicating incomplete removal of progestins during wastewater treatment processing. This activity poses a continuing risk for the aquatic environment. By contrast, anti-progestagenic activities showed better removal efficiency in WWTPs compared to progestagenic agonistic activities. Anti-progestagenic activities were found in only three of six effluents and ranged from 0.26 to 2.1 ng/L mifepristone EQs. We explained most of the progestagenic activity in municipal WWTP effluents by the presence of synthetic progestins and progesterone, which contributed 65-96% of such activity in samples where no antagonistic activity was found. The progestins medroxyprogesterone acetate, megestrol acetate and progesterone contributed most to the progestagenic activity detected in municipal effluents. Anti-progestagenic activities were found in some municipal effluents, but no causative agents were revealed because two analysed selective progesterone receptor modulators (SPRMs) with anti-progestagenic activities, mifepristone and ulipristal acetate, were not present in the effluents.

Concepts: Wastewater, Hormonal contraception, Water, Selective progesterone receptor modulator, Water pollution, Progestin, Progesterone, Sewage treatment