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With the basic principle of separating control and data planes, software defined networking (SDN) has emerged as a promising paradigm. The separation generates a variety of scaling concerns (e.g., higher reaction time, overhead on the controller). As more nodes are connected in the SDN, the routing process becomes tedious. The traditional reactive method of routing provides dynamic link finding through network state information, which leads to high computation overhead on the SDN controller and low link utilization and throughput. The proactive method in the source path routing method (SPRM) simply provides one backup path for routing. But this is not efficient in handling link failures. Our focus is on reducing the memory overhead caused by link failures in the data and control plane, through the proposed modified source path routing model (SPRM) technique. This method also improves the execution time by making the proactive phase compute k paths and allowing the reactive phase to choose an efficient path from the pre-installed k paths, thereby choosing a backup path which is next best efficient for routing. Our simulation studies show an improvement of 22.5% in link utilization and throughput in the presence of link failures for the proposed method. [ABSTRACT FROM AUTHOR]

Uterine leiomyomas (ULs) are the most common benign smooth muscle cell steroid-dependent tumors that occur in women of reproductive age. Progesterone (P4) is a major hormone that promotes the ULs development and growth. P4 action in ULs is mediated mainly by its nuclear progesterone receptors (PGRs), although rapid non-genomic responses have also been observed. Data on the membrane progesterone receptors (mPRs) regulated signaling pathways in ULs in the available literature is still very limited. One of the essential characteristics of ULs is the excessive production of extracellular matrix (ECM). P4 has been shown to stimulate ECM production and collagen synthesis in ULs. Recent research demonstrated that, despite their benign nature, ULs may present with abnormal vasculature. P4 has been shown to regulate angiogenesis in ULs through the upregulation of vascular endothelial growth factor (VEGF) and by controlling the secretion of permeability factors. This review summarizes the key findings regarding the role of PGRs and mPRs in ULs, especially highlighting the potential ECM and angiogenesis modulation by P4. An increased understanding of this mechanistic role of nuclear and specifically mPRs in the biology of P4-modulated ECM and angiogenesis in the growth of ULs could turn out to be fundamental for developing effective targeted therapies for ULs. [ABSTRACT FROM AUTHOR]

Uterine fibroids (UFs) are the most important benign neoplastic threat to women's health worldwide, with a prevalence of up to 80% in premenopausal women, and can cause heavy menstrual bleeding, pain, and infertility. Progesterone signaling plays a crucial role in the development and growth of UFs. Progesterone promotes the proliferation of UF cells by activating several signaling pathways genetically and epigenetically. In this review article, we reviewed the literature covering progesterone signaling in UF pathogenesis and further discussed the therapeutic potential of compounds that modulate progesterone signaling against UFs, including selective progesterone receptor modulator (SPRM) drugs and natural compounds. Further studies are needed to confirm the safety of SPRMs as well as their exact molecular mechanisms. The consumption of natural compounds as a potential anti-UFs treatment seems promising, since these compounds can be used on a long-term basis—especially for women pursuing concurrent pregnancy, unlike SPRMs. However, further clinical trials are needed to confirm their effectiveness. [ABSTRACT FROM AUTHOR]

Endometriosis is a chronic, estrogen-dependent, inflammatory disease associated with pelvic pain, infertility, impaired sexual function, and psychological suffering. Therefore, tailored patient management appears of primary importance to address specific issues and identify the appropriate treatment for each woman. Over the years, abundant research has been carried out with the objective to find new therapeutic approaches for this multifaceted disease. This narrative review aims to present the latest advances in the pharmacological management of endometriosis. In particular, the potential role of GnRH antagonists, selective progesterone receptor modulators (SPRMs), and selective estrogen receptors modulators (SERMs) will be discussed. We performed a literature search in PubMed and Embase, and selected the best quality evidence, giving preference to the most recent and definitive original articles and reviews. Medical therapy represents the cornerstone of endometriosis management, although few advances have been made in the last decade. Most studies have focused on the evaluation of the efficacy and safety of GnRH antagonists (plus add-back therapy in cases of prolonged treatment), which should be used as second-line treatment options in selected cases (i.e. non-responders to first-line treatments). Further studies are needed to identify the ideal treatment for women with endometriosis. [ABSTRACT FROM AUTHOR]

Uterine fibroids (UFs) are the most important benign neoplastic threat to women’s health worldwide, with a prevalence of up to 80% in premenopausal women, and can cause heavy menstrual bleeding, pain, and infertility. Progesterone signaling plays a crucial role in the development and growth of UFs. Progesterone promotes the proliferation of UF cells by activating several signaling pathways genetically and epigenetically. In this review article, we reviewed the literature covering progesterone signaling in UF pathogenesis and further discussed the therapeutic potential of compounds that modulate progesterone signaling against UFs, including selective progesterone receptor modulator (SPRM) drugs and natural compounds. Further studies are needed to confirm the safety of SPRMs as well as their exact molecular mechanisms. The consumption of natural compounds as a potential anti-UFs treatment seems promising, since these compounds can be used on a long-term basis—especially for women pursuing concurrent pregnancy, unlike SPRMs. However, further clinical trials are needed to confirm their effectiveness.

The use of ulipristal acetate (UPA) was indicated for the treatment of uterine fibroids. Following UPA suspension in March 2020, some patients presented worsening and required surgery. We aimed to identify patients at high-risk for undergoing surgery after UPA suspension. We evaluated 85 women receiving intermittent UPA treatment until March 2020. Following UPA suspension, patients received other medical treatments or surgery. The clinico-pathological features were recoded and a quality of life health survey was completed by patients at the time of UPA suspension and at 6-months thereafter. After the suspension of UPA, 17 of the 85 patients receiving intermittent UPA (20%) required surgery, and 68 (80%) required other medical treatments. Patients who underwent surgery were younger and had greater fibroid volume. In our series, 20% of clinically stable patients receiving intermittent UPA required surgery following UPA suspension. These women should be considered for future medical strategies [ABSTRACT FROM AUTHOR]

Introduction: Endometriosis is an estrogen-dependent disease that gives rise to pelvic pain and infertility. Although estroprogestins and progestins currently stand as the first-line treatments for this condition, demonstrating efficacy in two-thirds of patients, a significant portion of individuals experience only partial relief or symptom recurrence following the cessation of these therapies. The coexistence of superficial, deep endometriosis, and ovarian endometriomas, as three distinct phenotypes with unique pathogenetic and molecular characteristics, may elucidate the current heterogeneous biological response to available therapy., Areas Covered: The objective of this review is to furnish the reader with a comprehensive summary pertaining to phase II-III hormonal treatments for endometriosis., Expert Opinion: Ongoing research endeavors are directed toward the development of novel hormonal options for this benign yet debilitating disease. Among them, oral GnRH antagonists emerge as a noteworthy option, furnishing rapid therapeutic onset without an initial flare-up; these drugs facilitate partial or complete estrogen suppression, and promote prompt ovarian function recovery upon discontinuation, effectively surmounting the limitations associated with previously employed GnRH agonists. Limited evidence supports the use of selective estrogen and progesterone receptor modulators. Consequently, further extensive clinical research is imperative to garner a more profound understanding of innovative targets for novel hormonal options.

Evidence from different sources sustains a pro-oncogenic role of hormones, estrogens and progestogens, on the breast. The issue is of interest for young women, who are exposed to the hormonal changes imposed by the ovarian cycle and, often, take hormones with contraceptive purposes. Experimental and clinical studies show that both estrogens and progesterone are involved in mammary development during puberty and lactation, the changes being observed across mammalian species, including humans. Estrogen receptors, and more particularly the alpha isoform, participate in molecular processes of stem cells differentiation and epithelial proliferation through paracrine actions implicating growth factors. Progesterone also contributes through paracrine mechanisms involving one member of the tumor necrosis factor (TNF) family, the receptor activator of nuclear factor κB ligand (RANKL) and its receptor (RANK). Epidemiological studies have found that the length of the exposure to endogenous hormones, as determined by an early menarche or a late menopause, is a risk factor for breast cancer. Additional evidence has derived from studies with compounds modulating the estrogen or the progesterone receptors. Selective estrogen receptor modulators (SERM), like tamoxifen, have been shown to decrease the risk of breast cancer in both pre- and post-menopausal women. Aromatase inhibitors, which drastically reduce the levels of circulating estrogens, have reproduced the findings. The selective progesterone receptor modulators (SPRM) have been less investigated and issues concerning safety have arisen. These observations have interest for young women. High-risk women may consider the use of SERMs, for example, to reduce their risk. Much more common is the case of women who take hormones for contraception. The goal of the present article is twofold: i) to summarize the actual knowledge of the mechanisms implicating estrogens and progestogens on the risk for breast cancer and ii) to provide rationality for the debate about potential cancer risk of hormonal contraceptives, frequently used by premenopausal women. [ABSTRACT FROM AUTHOR]

Uterine anatomy and uterine fibroids (UFs) characteristics have been classically considered as almost a unique issue in gynecology and reproductive medicine. Nowadays, the management of UF pathology is undergoing an important evolution, with the patient's quality of life being the most important aspect to consider. Accordingly, surgical techniques and aggressive treatments are reserved for only those cases with heavy symptomatology, while the clinical diagnostic based on size and number of UFs remains in a second plane in these situations. Moreover, the development of several noninvasive surgical techniques, especially the appearance of ulipristal acetate as a medical etiological treatment, has substantially changed the clinical indications. As a consequence, after almost 2 decades without relevant updates, it has been necessary to update the protocols for the management of UFs in the Spanish Society of Gynecology and Obstetrics twice. Accordingly, we believe that it is necessary to translate our experience to protocolize the medical care for patients with UFs, incorporating these new therapeutic options and selecting the best treatment for them. We highlight the importance of achieving the patient's goals and decisions by improving the clinical diagnosis for these type of pathologies, allowing enhanced personalized treatments, as well as the reduction of potential risks and unnecessary surgeries. [ABSTRACT FROM AUTHOR]

Aim: To assess the attitudes of gynecologists toward symptomatic fibroids and analyze which factors influence their choice of treatment.Material and Method: We surveyed the attitude of Belgian gynecologists toward patients' cases. We used a vignette of a woman with symptomatic fibroids and modified 3 factors: her age, her parity and her desire for pregnancy, thereby establishing 12 different cases. We ensured that each gynecologist (n=1437) received one case, chosen randomly, by email. The gynecologists were asked whether and how they would treat the patient.Results: Replies were received from 337 gynecologists (a 23% response rate). Of the 337, 116 (34%) would prescribe a medical treatment only; in this group, 29% specified acetate ulipristal a selective progesterone receptor modulator (SPRM) and 27% indicated progestins. Of the sample of 337 responders, another 116 (34%) would begin with medical treatment (70% an SPRM) and then proceed to surgery. Of the 337 gynecologists, 75 (22%) would perform surgery only. The preferred surgical treatments were myomectomy (53/75; 71%) and hysterectomy (19/75; 25%) when surgery was suggested as a first step, and myomectomy (91/115; 79%) and hysterectomy (18/115; 16%) when it was preceded by medical treatment. The choice of treatment varied significantly in relation to the 12 vignettes (p<0.01). When we grouped the vignettes there was no significant variation in relation to age or parity, but a there was significant variation (p<0.001) in relation to desire to achieve pregnancy.Conclusion: We observed that, in women with symptomatic fibroids, the desire retain fertility is respected. Moreover, SPRM is increasingly used for symptomatic patients. [ABSTRACT FROM AUTHOR]

Cell-based kinetic studies of ligand or candidate drug binding to membrane proteins have produced affinity and kinetic values that are different from measurements using purified proteins. However, ligand binding to fixated cells whose membrane constituents (e.g., proteins and their glycosylated forms) are partially connected by a cross-linking reagent has not been compared to that to live cells. Under the same experimental conditions for the LigandTracer method, we measured the interactions of fluorophore-labeled lectins and antibody molecules with glycans at HFF cells and the human epithelial growth receptor 2 at SKBR3 cells, respectively. In conjunction with surface plasmon resonance microscopy, the effects of labels and cell/sub-cell heterogeneity on binding kinetics were investigated. Our results revealed that, for cell constituents whose structures and functions are not closely dependent on cell viability, the ligand binding kinetics at fixated cells is only slightly different from that at live cells. The altered kinetics is explained on the basis of a less mobile receptor confined in a local environment created by partially interconnected protein molecules. We show that cell/sub-cell heterogeneity and labels on the ligands can alter the binding reaction more significantly. Thus, fixating cells not only simplifies experimental procedures for drug screening and renders assays more robust but also provides reliable kinetic information about drug binding to cell constituents whose structures are not changed by chemical fixation.

This paper presents a new model for improving the pointing accuracy of a telescope. The Denavit–Hartenberg (D–H) convention was used to perform an error analysis of the telescope's kinematics. A kinematic model was used to relate pointing errors to mechanical errors and the parameters of the kinematic model were estimated with a statistical model fit using data from two large astronomical telescopes. The model illustrates the geometric errors caused by imprecision in manufacturing and assembly processes and their effects on the pointing accuracy of the telescope. A kinematic model relates pointing error to axis position when certain geometric errors are assumed to be present in a telescope. In the parameter estimation portion, the semi-parametric regression model was introduced to compensate for remaining nonlinear errors. The experimental results indicate that the proposed semi-parametric regression model eliminates both geometric and nonlinear errors, and that the telescope's pointing accuracy significantly improves after this calibration. [ABSTRACT FROM AUTHOR]

Women with benign heavy menstrual bleeding have the choice of a number of medical treatment options to reduce their blood loss and improve quality of life. The role of the clinician is to provide information to facilitate women in making an appropriate choice. Unfortunately, many options can be associated with hormonal side effects, prevention of fertility and lack of efficacy, leading to discontinuation and progression to surgical interventions. Herein, we discuss the various options currently available to women, including antifibrinolytics, nonsteroidal anti-inflammatory preparations, oral contraceptive pills and oral, injectable and intrauterine progestogens. In addition, we describe the more novel option of selective progesterone receptor modulators and their current benefits and limitations. [ABSTRACT FROM AUTHOR]

Uterine fibroids (UF) are benign smooth muscle neoplasm of uterus that have a significant impact on a woman's quality of life as they perturb hormonal homeostasis resulting in heavy menstrual bleeding, impaired fertility, pregnancy complications and loss. UF can be surgically removed through invasive procedures, but their recurrence rate is often high. Progesterone receptor (PR) has an imperative role in UF management. Mifepristone, ulipristal acetate (UPA) and asoprisnil (ASO) are some selective progesterone receptor modulators (SPRMs), acts on PR, but due to their side effects in long term use, they were withdrawn from the market. Hence, there is a dire need for novel, highly efficient with least side effects, therapeutics for the treatment of UF. To contribute toward the drug discovery for UF, we made an extensive structural comparison of reported PR crystal structures, also elucidated the binding modes of four existing SPRMs against human PR through ensemble docking approach. Our studies revealed the presence of 5 highly repeating water molecules that has an important role in ligand binding and structural stability. Our ensemble docking and MD simulation revealed that studied ligands have preferential selectivity toward the specific conformation of PR. It is anticipated that our study will be a useful resource to all the drug discovery scientists who are engaged in the identification of lead molecules against UF.

Objective To evaluate changes in proliferating and apoptotic markers of myoma tissue from patients treated with a selective progesterone receptor modulator (SPRM) or GnRH agonist by measuring expression of PDGF-A mRNA, IGF-1 mRNA, bcl-2 mRNA, and PCNA and caspase-3 protein. Study design Between December 2013 and July 2014, women with symptomatic leiomyoma were divided into control (no treatment before surgery), SPRM (treatment with ulipristal acetate [SPRM] for 3 months before surgery), and GnRHa (treatment with leuprolide acetate [GnRH agonist] for 3 months before surgery) groups. Tissue specimens were collected from the myoma core and normal myometrium of all patients. The expression of mRNA and protein was assessed by quantitative real-time reverse transcriptase-polymerase chain reaction and Western blot. Results A total of 38 patients were enrolled (control group, n = 14; SPRM group, n = 13; GnRHa group, n = 11). PDGF-A mRNA expression was lower in both the myoma core and normal myometrium tissues of the SPRM compared with the control group, but there was no difference between the control and GnRHa group. There were also no group differences in bcl-2 mRNA or IGF-1 mRNA expression. Both PCNA and caspase-3 protein expression were higher in the leiomyoma tissue of the SPRM compared with the control group, but there was no difference between the control and GnRHa groups in the expression of either protein. Conclusion Both proliferation and apoptosis were increased in the leiomyoma of patients after SPRM treatment, but there was no change following GnRH agonist treatment, in vivo . However, PDGF-A mRNA was decreased after SPRM treatment, indicating a dual effect of progesterone on the regulation of growth factors. Furthermore, there was an increase in caspase-3 protein, but not bcl-2 mRNA, expression in the SPRM group suggesting that SPRM may exert its effects in pathways other than the bcl-2 apoptotic pathway. [ABSTRACT FROM AUTHOR]

Although it has been known for a long time that uterine fibroids respond to changes in sex steroid concentrations, it is the availability of selective progesterone receptor modulators such as ulipristal acetete that has provided the gynecologist with a novel option for medical management of uterine fibroids. Ulipristal acetate is presently licensed in Europe for use in women with symptomatic fibroids up to 3 months prior to surgery and has demonstrated good clinical efficacy and safety for this indication. Future trials will define the long-term safety of this drug and its role in medical management of uterine fibroids. [ABSTRACT FROM AUTHOR]

In addition to the estrogen receptor, the progesterone receptor plays an important role in the growth of uterine fibroids. Several selective progesterone receptor modulators (SPRMs) have been evaluated for medical treatment of uterine fibroids and, because of safety issues, some molecules were stopped during clinical development. However, in 2012, ulipristal acetate received the approval for a pre-surgical treatment of uterine fibroids. Clinical trials with ulipristal acetate for long-term medical treatment of uterine fibroids are ongoing. This review article describes the action of SPRMs at the progesterone receptor level and the mechanism of action on the fibroid tissue. A review of the published clinical trials is performed, including the current evidence of efficacy on uterine fibroid symptom management, size reduction and tolerability. The therapeutic potential of SPRMs for uterine fibroids is discussed. [ABSTRACT FROM AUTHOR]

Résumé: Les selective progesterone receptor modulators (SPRM) sont des molécules agonistes et/ou antagonistes du récepteur de la progestérone. Ils sont responsables d’une anovulation, d’une aménorrhée et d’une baisse des prostaglandines, ce qui entraîne une amélioration des douleurs et une régression des lésions dans l’endométriose. Au niveau endométrial, un aspect particulier, le progesterone receptor modulator-associated endometrial change (PAEC), suscite des études complémentaires pour vérifier son innocuité. Cependant, du fait de l’absence d’hypo-œstrogénie et d’effet métabolique avec ces molécules, il est très probable que les SPRM prendront dans un futur proche une place primordiale dans le traitement de l’endométriose. [ABSTRACT FROM AUTHOR]

Objective: To discuss the mechanism of action of selective progesterone receptor modulators (SPRMs) and summarize the preclinical and clinical efficacy and safety data supporting the potential use of these compounds for gynecologic indications. Design: Relevant publications from 2005 onward were identified using a PubMed search. Additional relevant articles were identified from citations within these publications. Setting: None. Patient(s): None. Intervention(s): None. Main Outcome Measure(s): None. Result(s): Mifepristone was first developed as a progesterone receptor antagonist and licensed for pregnancy termination because of the unique property of this compound to terminate pregnancy when associated with prostaglandins. Then SPRMs were developed, and among those ulipristal acetate, an efficient emergency contraceptive. Because SPRMs effectively inhibit endometrial proliferation and reduce endometriotic lesions in animal models, this suggests a possible role in the treatment of endometriosis in humans. Finally, a number of double-blind, randomized, placebo-controlled trials have demonstrated the efficacy of asoprisnil, mifepristone, telapristone acetate, and ulipristal acetate in reducing leiomyoma and uterine volume, and suppressing bleeding in women with uterine fibroids. Conclusion(s): Mifepristone in combination with prostaglandins has been licensed for pregnancy termination because of its unique ability is this area. Ulipristal acetate is available for emergency contraception. Several SPRMs hold further promise as an effective medical therapy for patients suffering from endometriosis and leiomyoma. [ABSTRACT FROM AUTHOR]

Endometriosis is an often painful disorder in which the endometrial glands and stroma grow outside the uterus. The disease affects women’s quality of life and is a common cause of infertility. In this review, we describe promising new developments in the field based on in vitro assays and rodent models, each of which has the potential to be beneficial in the treatment of this disease. We will specifically describe the role of anti-inflammatory drugs, selective estrogen, or progesterone modulators, statins, antiangiogenic agents, and the potential for targeting stem cells as likely methods to hone in and eliminate endometriosis. The most promising of these potential therapies are currently slated for further testing in both rodent and nonhuman primate trials. [ABSTRACT FROM PUBLISHER]

The two main contraceptive methods are the combined pill and the intrauterine device. In several countries, sterilization is a commonly used alternative. The current goals of contraception remain to achieve effective, accessible, reversible, and well-tolerated birth control for everyone. Despite progress, these goals have not been reached. To achieve these goals, it is mandatory to create new hormonal combinations and to discover new contraceptive targets. Recent innovations associate the development of new progestogens, selective progesterone receptor modulators, and the creation of new contraceptive combinations. Other innovations involve the use of natural estrogens but also optimizing existing treatment regimens and doses, as well as the development of new methods of emergency contraception. Finally, a major step will be to invent an efficient contraceptive that carries the lowest possible risk associated with methods protecting against sexually transmitted diseases. In the future, in relation to progress in the fields of genomics, proteomics, and immunology, new methods of contraception will be developed. These methods will be more targeted and will eventually be nonhormonal and independent of sexual activity. [ABSTRACT FROM AUTHOR]

Selective progesterone receptor modulators (SPRM) represent a new class of synthetic steroids, which can interact with the progesterone receptor (PR) and can exert agonist, antagonist or mixed effects on various progesterone target tissues in vivo. This review evaluates the actual and potential usefulness of SPRMs in gynaecology. [ABSTRACT FROM AUTHOR]

Abstract: Progesterone receptor (PR) modulators are used in contraception and post-menopausal hormone therapy, and are under clinical development for reproductive disorders such as uterine fibroids and endometriosis. Development of tissue selective PR modulators (SPRMs) with reduced side effects and improved pharmacology represents a large unmet medical need in the area of women’s health. One approach to addressing this need is to focus on the two PR isoforms PR-A and PR-B. In vitro and in vivo studies have revealed both distinct as well as overlapping gene regulation and functional responses of the two PR isoforms that suggests that PR-A selective modulators may retain a desired biological profile. We have identified a chemical series of 4-(4-chlorophenyl)-substituted piperazine carbimidothioic acid esters (PCEs) that have partial PR agonist activity and selectively activate some PR-A isoform regulated genes in T47D cells. However, full microarray analysis in these cells does not predict a global isoform selective profile for these compounds, but rather a unique gene-selective profile is observed relative to steroidal progestins. Using multiplexed peptide interaction profiling and co-activator recruitment assays we find that the mechanism of partial agonism is only partly defined by the ability to recruit known co-activators or peptides but also depends on the cell and promoter context of the gene under investigation. The data demonstrate global consequences of mechanistic and functional differences that can lead to selective biological responses of novel steroid receptor modulators. [Copyright &y& Elsevier]

Abstract: Progesterone receptor modulators (PRMs) play an important role in women''s health. They are widely used in oral contraception or hormone therapy, and provide an attractive treatment approach for gynecological disorders such as uterine leiomyomas, endometriosis or breast cancer. Due to the broad range of activities, various studies were conducted to assess progesterone receptor antagonists (PAs) and selective progesterone receptor modulators (SPRMs) with respect to progesterone receptor (PR) agonistic and antagonistic activities in vivo. These properties are not always adequately reflected in classical in vitro models, especially differences in the agonistic potential of SPRMs, such as asoprisnil, J1042, and J912, and mixed antagonists, such as mifepristone, are not sufficiently substantiated. The effects of PRMs upon gene expression in progesterone target tissues such as breast epithelium and uterus are poorly understood. This study compares the properties of PR ligands using mammalian two-hybrid assays and gene expression profiling. The protein–protein interaction analyses in HeLa cells provide for specific ligand-induced PR conformations, whereas Affymetrix GeneChip HG-U133Plus2.0 analyses in T47D breast cancer cells indicate the transcriptional activity on the level of target genes. The analyses comprise the pure agonist R5020, the non-steroidal PR modulator PRA-910, SPRMs (J1042, asoprisnil, J912), the mixed antagonist mifepristone, classical antagonists (onapristone, ZK 137316) and the pure antagonist lonaprisan to consider all types of ligands described before. Marginal differences were identified in coactivator interaction profiles at all, but significant differences between SPRMs and PR antagonists (PAs) were observed in recruiting the LXXLL-motif containing peptide (LX-H10), very similar to in vivo activities in endometrial transformation in the rabbit (McPhail test). Global gene expression profiles demonstrated progesterone-independent effects for all PR modulators examined and emphasised similarities of asoprisnil and J1042 compared to J912 and all types of PR antagonists. In summary, the data support the popular concept of PR modulator classification in agonists, selective progesterone receptor modulators, mixed and pure antagonists. It further refines previous classification models and accentuates unique effects for each PR modulator. [Copyright &y& Elsevier]

Abstract: Recently, a new class (often referred to as SPRMs: selective progesterone receptor modulators) of progesterone receptor ligands with mixed agonist/antagonist properties has been described. Such compounds are envisaged, for example, as treatment for endometriosis, uterine fibroids, and leiomyomas. Existing SPRMs include Asoprisnil 1 and Uliprisnil acetate 2. In our hands, however, these compounds proved to have a predominantly or exclusively antagonistic in vitro profile, which may make this type of compound less attractive, for example, as contraceptives. We therefore aimed at a class of mixed-profile compounds that would show a more evenly balanced agonist/antagonist profile. A novel class of 11β-[4-(heteroaryl)phenyl]-substituted pregnanes was identified that displayed the desired balance. Contrary to known SPRMs, this novel class of MPP (mixed-profile progestagen) was found to have a truly mixed activity, including a sizeable agonist component. [Copyright &y& Elsevier]

Third-generation oral contraceptives are an association of low-dose ethinyl estradiol and potent testosterone-derived progestins, developed in order to improve general and vascular tolerance. They are highly efficient and well tolerated by most users. Their extensive use has provided different key information: oral contraceptives (as well as non-oral ethinyl estradiol-containing contraceptives) can be used in women under the age of 35 years with well-controlled metabolic risk factors and high familial risk of breast cancer. On the other hand, ethinyl-estradiol containing contraceptives are not indicated in women with a high risk of deep venous thrombosis, or noncontrolled metabolic and vascular risk factors (including being over the age of 35 years or cigarette smoking), or with a history of breast cancer. Progestin-only contraception is not well tolerated owing to bleeding. Future hormonal contraception for women with a high vascular risk may contain nontestosterone-derived progestins and 17β estradiol, or antiprogestins. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of the selective progesterone receptor modulator, telapristone acetate (CDB-4124), on endometrial biology and reproductive outcomes. Ovariectomized and hormone-treated CD1 female mice, CD1 female mice with xenotransplants of reconstructed human endometrial tissue, mated wildtype female mice, and cultured human endometrial stromal cells (hESCs) were treated with CDB-4124, followed by the assessment of endometrial cell deoxyribonucleic acid (DNA) proliferation, stromal decidual response, and embryo implantation., Design: Experimental study., Setting: Academic research laboratory., Patients: Healthy volunteer women from the community were recruited for endometrial biopsies., Animals: CD1 out-bred mice (Charles River Laboratories) and nude mice, NU/J (Jackson Laboratories, Bar Harbor, ME)., Intervention: Treatment of mice and hESCs with CDB-4124., Main Outcome Measure: The effect of CDB-4124 on endometrial cell morphology and DNA synthesis, decidual response, and mouse embryo implantation., Results: CDB-4124 inhibited estradiol-induced epithelial DNA synthesis in the mouse uterus and xenotransplanted human endometrium. This antiproliferative effect was less than that of progesterone (P4) and was observed when CDB-4124 was administered alone or concomitantly with P4. In the uterine epithelium, CDB-4124 acted as a P4 agonist and partial antagonist. In contrast, CDB-4124 acted as a complete P4 antagonist in the uterine stroma, where it blocked P4's action to induce a decidual response in the pseudopregnant mouse uterus and wildtype mouse uterus after copulation. In mated female mice, CDB-4124 impaired embryo implantation. Similarly, CDB-4124 inhibited the morphological and biochemical transformations of hESCs to decidual cells in vitro., Conclusion: CDB-4124 exerts mixed P4 antagonistic/agonistic effects in the human and mouse endometrium, which result in failed embryo implantation because of the absence of stromal decidualization., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Surface plasmon resonance microscopy (SPRM) is a powerful label-free imaging technique with spatial resolution approaching the optical diffraction limit. The high sensitivity of SPRM to small changes in index of refraction at an interface allows imaging of dynamic protein structures within a cell. Visualization of subcellular features, such as focal adhesions (FAs), can be performed on live cells using a high numerical aperture objective lens with a digital light projector to precisely position the incident angle of the excitation light. Within the cell-substrate region of the SPRM image, punctate regions of high contrast are putatively identified as the cellular FAs. Optical parameter analysis is achieved by application of the Fresnel model to the SPRM data and resulting refractive index measurements are used to calculate protein density and mass. FAs are known to be regions of high protein density that reside at the cell-substratum interface. Comparing SPRM with fluorescence images of antibody stained for vinculin, a component in FAs, reveals similar measurements of FA size. In addition, a positive correlation between FA size and protein density is revealed by SPRM. Comparing SPRM images for two cell types reveals a distinct difference in the protein density and mass of their respective FAs. Application of SPRM to quantify mass can greatly aid monitoring basic processes that control FA mass and growth and contribute to accurate models that describe cell-extracellular interactions.

Background: Aberrant progesterone signaling has been demonstrated in mechanistic studies to be a shared common pathway in fibroids and endometriosis. Progesterone receptor modulation with the selective progesterone receptor modulator (SPRM) ulipristal may decrease pain associated with endometriosis., Case: A 25-year-old nulligravidae with endometriosis-related pelvic pain refractory to medical and surgical intervention was administered 15mg ulipristal every other day for 3 months. Daily pain scores and bleeding diary were recorded and serum chemistries and hormone levels were checked prior to, during, and after treatment. Pre-treatment and surveillance endometrial biopsy specimens were examined for histology and stained for estrogen and progesterone receptor status. During therapy, pain scores decreased to a median of 0 (P<0.05) and the patient became amenorrheic. Surveillance endometrial biopsy demonstrated SPRM-associated endometrial changes that appeared strikingly similar to simple hyperplasia and resolved with ulipristal discontinuation. Immunohistochemical evaluation demonstrated the presence of estrogen and progesterone receptors before and during ulipristal treatment., Conclusions: Progesterone receptor modulation with ulipristal substantially improved pain symptoms in a patient with treatment-refractory endometriosis. SPRM-associated changes in the endometrium closely mimicked hyperplasia, developed after less than three months of treatment, and resolved after discontinuation of ulipristal and induction of withdrawal bleed.

Surface plasmon resonance (SPR) spectroscopy is a rapidly developing technique for the study of ligand binding interactions with membrane proteins, which are the major molecular targets for validated drugs and for current and foreseeable drug discovery. SPR is label-free and capable of measuring real-time quantitative binding affinities and kinetics for membrane proteins interacting with ligand molecules using relatively small quantities of materials and has potential to be medium-throughput. The conventional SPR technique requires one binding component to be immobilised on a sensor chip whilst the other binding component in solution is flowed over the sensor surface; a binding interaction is detected using an optical method that measures small changes in refractive index at the sensor surface. This review first describes the basic SPR experiment and the challenges that have to be considered for performing SPR experiments that measure membrane protein-ligand binding interactions, most importantly having the membrane protein in a lipid or detergent environment that retains its native structure and activity. It then describes a wide-range of membrane protein systems for which ligand binding interactions have been characterised using SPR, including the major drug targets G protein-coupled receptors, and how challenges have been overcome for achieving this. Finally it describes some recent advances in SPR-based technology and future potential of the technique to screen ligand binding in the discovery of drugs. This article is part of a Special Issue entitled: Structural and biophysical characterisation of membrane protein-ligand binding., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Fibroids have a high prevalence (approaching 50%) in the female population. Although they are a benign entity, they represent a health problem of considerable magnitude, causing hemorrhaging, pain and sterility. Surgical treatment is currently safe and effective, but in recent decades numerous less invasive alternatives have appeared, such as uterine artery embolization and thermal ablation (HIFU and radiofrequency). New possibilities for medical treatment have also emerged, such as GnRh analogues, aromatase inhibitors and selective progesterone receptor modulators (SPRMs). SPRMs act through progesterone receptors and behave as agonists or antagonists in various target organs. Among them, ulipristal acetate (UA) inhibits the proliferation and induction of apoptosis and cell death pathways in leiomyoma cells, translating at the clinical level to smaller fibroids and lower uterine volumes, with no significant side effects. UA also produces amenorrhea in most patients. Randomized, phase III (PEARL I and II) clinical trials have shown the efficacy and security of UA versus placebo and leuprolide acetate (LA). UA is similar to LA, and superior to placebo in controlling bleeding and decreasing the size of the fibroid, with fewer side effects than LA. The safety and tolerance of UA have been satisfactory. UA is a reality in the preoperative treatment of fibroids, with broad potential for further development., (Copyright © 2013 Elsevier España, S.L. All rights reserved.)