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Pharmaceuticals (Basel, Switzerland) Sep 2023In this scoping review, we sought to identify published studies evaluating the drugs currently used in the treatment of endometriosis-related pelvic pain, with... (Review)
Review
BACKGROUND
In this scoping review, we sought to identify published studies evaluating the drugs currently used in the treatment of endometriosis-related pelvic pain, with reflection on their chemical properties, pharmacokinetics, safety profile, and clinical efficacy.
METHODS
A literature search was conducted with the use of the PubMed and EMBASE electronic databases, focusing on identifying articles published in English between January 1990 and 2023.
RESULTS
Based on the included studies, current therapy options for the treatment of endometriosis-related pain identified and reviewed in this article were: (1) non-steroidal anti-inflammatory drugs; (2) combined oral contraceptive (COCs); (3) progestins; (4) gonadotropin-releasing hormone agonists and antagonists; (5) aromatase inhibitors (AIs); (6) selective estrogen and progesterone receptor modulators; and (7) levonorgestrel-intrauterine device.
CONCLUSIONS
Based on the published evidence, clinicians should consider NSAIDs, COCs, and progestins as the first-line medical therapies. Compared with second-line options, such as GnRH agonists/antagonists or AIs, the abovementioned first-line options are well tolerated, efficacious, and exhibit lower overall price. Future research priorities should be to identify novel target therapies and to evaluate the effects of available drugs through different routes of administration.
PubMed: 37765123
DOI: 10.3390/ph16091315 -
Frontiers in Endocrinology 2023Gonadotropin-releasing hormone antagonist (GnRH-ant) protocol is widely used in the world for controlled ovarian hyperstimulation (COH). However, previous studies have...
INTRODUCTION
Gonadotropin-releasing hormone antagonist (GnRH-ant) protocol is widely used in the world for controlled ovarian hyperstimulation (COH). However, previous studies have shown that pregnancy outcomes of fresh embryo transfer with GnRH-ant protocol are not ideal. Current studies have demonstrated the value of growth hormone (GH) in improving the pregnancy outcome of elderly women and patients with diminished ovarian reserve, but no prospective studies have confirmed the efficacy of GH in fresh embryo transfer with GnRH-ant protocol, and its potential mechanism is still unclear. This study intends to evaluate the impact of GH on IVF/ICSI outcomes and endometrial receptivity of patients undergoing GnRH-ant protocol with fresh embryo transfer, and preliminarily explore the possible mechanism.
METHODS
We designed a randomized controlled trial of 120 infertile patients with normal ovarian response (NOR) who will undergo IVF/ICSI from April 2023 to April 2025, at Department of Reproductive Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The patients will be divided into the depot gonadotropin-releasing hormone agonist (GnRH-a) protocol group, GnRH-ant protocol control group, and GnRH-ant protocol plus GH intervention group at a ratio of 1:1:1 by block randomization design. Patients will be followed on enrollment day, trigger day, embryo transfer day, 7 days after oocytes pick-up, 15 days after embryo transfer, 28 days after embryo transfer, and 12 weeks of gestation. The primary outcome is the ongoing pregnancy rate. Secondary outcomes include the gonadotropin dosage, duration of COH, endometrial thickness and pattern, luteinizing hormone, estradiol, progesterone level on trigger day, numbers of retrieved oocytes, high-quality embryo rate, biochemical pregnancy rate, clinical pregnancy rate, implantation rate, ectopic pregnancy rate, early miscarriage rate, multiple pregnancy rate and incidence of moderate and severe ovarian hyperstimulation syndrome. The endometrium of certain patients will be collected and tested for endometrial receptivity.
ETHICS AND DISSEMINATION
The study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology [approval number: TJ-IRB20230236; approval date: February 10, 2023]. The research results will be presented at scientific/medical conferences and published in academic journals.
CLINICAL TRIAL REGISTRATION
Chinese Clinical Trial Registry; identifier: ChiCTR2300069397.
Topics: Aged; Humans; Female; Pregnancy; Growth Hormone; Pilot Projects; Sperm Injections, Intracytoplasmic; Human Growth Hormone; Embryo Transfer; Endometrium; Hormone Antagonists; Gonadotropin-Releasing Hormone; Randomized Controlled Trials as Topic
PubMed: 37727454
DOI: 10.3389/fendo.2023.1225121 -
Journal of Animal Science and... Sep 2023Exposure to bisphenol A (BPA), an environmental pollutant known for its endocrine-disrupting properties, during gestation has been reported to increase the risk of fetal...
BACKGROUND
Exposure to bisphenol A (BPA), an environmental pollutant known for its endocrine-disrupting properties, during gestation has been reported to increase the risk of fetal growth restriction (FGR) in an ovine model of pregnancy. We hypothesized that the FGR results from the BPA-induced insufficiency and barrier dysfunction of the placenta, oxidative stress, inflammatory responses, autophagy and endoplasmic reticulum stress (ERS). However, precise mechanisms underlying the BPA-induced placental dysfunction, and subsequently, FGR, as well as the potential involvement of placental ERS in these complications, remain to be investigated.
METHODS
In vivo experiment, 16 twin-pregnant (from d 40 to 130 of gestation) Hu ewes were randomly distributed into two groups (8 ewes each). One group served as a control and received corn oil once a day, whereas the other group received BPA (5 mg/kg/d as a subcutaneous injection). In vitro study, ovine trophoblast cells (OTCs) were exposed to 4 treatments, 6 replicates each. The OTCs were treated with 400 μmol/L BPA, 400 μmol/L BPA + 0.5 μg/mL tunicamycin (Tm; ERS activator), 400 μmol/L BPA + 1 μmol/L 4-phenyl butyric acid (4-PBA; ERS antagonist) and DMEM/F12 complete medium (control), for 24 h.
RESULTS
In vivo experiments, pregnant Hu ewes receiving the BPA from 40 to 130 days of pregnancy experienced a decrease in placental efficiency, progesterone (P4) level and fetal weight, and an increase in placental estrogen (E2) level, together with barrier dysfunctions, OS, inflammatory responses, autophagy and ERS in type A cotyledons. In vitro experiment, the OTCs exposed to BPA for 24 h showed an increase in the E2 level and related protein and gene expressions of autophagy, ERS, pro-apoptosis and inflammatory response, and a decrease in the P4 level and the related protein and gene expressions of antioxidant, anti-apoptosis and barrier function. Moreover, treating the OTCs with Tm aggravated BPA-induced dysfunction of barrier and endocrine (the increased E2 level and decreased P4 level), OS, inflammatory responses, autophagy, and ERS. However, treating the OTCs with 4-PBA reversed the counteracted effects of Tm mentioned above.
CONCLUSIONS
In general, the results reveal that BPA exposure can cause ERS in the ovine placenta and OTCs, and ERS induction might aggravate BPA-induced dysfunction of the placental barrier and endocrine, OS, inflammatory responses, and autophagy. These data offer novel mechanistic insights into whether ERS is involved in BPA-mediated placental dysfunction and fetal development.
PubMed: 37691111
DOI: 10.1186/s40104-023-00919-z -
Journal of Gynecology Obstetrics and... Nov 2023The French National College of Obstetricians and Gynecologists (CNGOF) published guidelines for managing endometriosis-associated pain in 2018. Given the development of...
The French National College of Obstetricians and Gynecologists (CNGOF) published guidelines for managing endometriosis-associated pain in 2018. Given the development of new pharmacological therapies and a review that was published in 2021, most national and international guidelines now suggest a new therapeutic approach. In addition, a novel validated screening method based on patient questionnaires and analysis of 109-miRNA saliva signatures, which combines biomarkers and artificial intelligence, opens up new avenues for overcoming diagnostic challenges in patients with pelvic pain and for avoiding laparoscopic surgery when sonography and MRI are not conclusive. Dienogest (DNG) 2 mg has been a reimbursable healthcare expense in France since 2020, and, according to recent studies, it is at least as effective as combined hormonal contraception (CHC) and can be used as an alternative to CHC for first-line treatment of endometriosis-associated pain. Since 2018, the literature concerning the use of DNG has grown considerably, and the French guidelines should be modified accordingly. The levonorgestrel intrauterine system (LNG IUS) and other available progestins per os, including DNG, or the subcutaneous implant, can be offered as first-line therapy, gonadotropin-releasing hormone (GnRH) agonists with add-back therapy (ABT) as second-line therapy. Oral GnRH antagonists are promising new medical treatments for women with endometriosis-associated pain. They competitively bind to GnRH receptors in the anterior pituitary, preventing native GnRH from binding to GnRH receptors and from stimulating the secretion of luteinizing hormone and follicle-stimulating hormone. Consequently, estradiol and progesterone production is reduced. Oral GnRH antagonists will soon be on the market in France. Given their mode of action, their efficacy is comparable to that of GnRH agonists, with the advantage of oral administration and rapid action with no flare-up effect. Combination therapy with ABT is likely to allow long-term treatment with minimal impact on bone mass. GnRH antagonists with ABT may thus be offered as second-line treatment as an alternative to GnRH agonists with ABT. This article presents an update on the management of endometriosis-associated pain in women who do not have an immediate desire for pregnancy.
Topics: Female; Humans; Endometriosis; Receptors, LHRH; Artificial Intelligence; Pelvic Pain; Gonadotropin-Releasing Hormone; Hormone Antagonists
PubMed: 37669732
DOI: 10.1016/j.jogoh.2023.102664 -
Brain and Behavior Nov 2023Studies have confirmed the salutary effects of progesterone (P4) on traumatic brain injury (TBI). This study investigated the beneficial effects of P4 via its receptors...
BACKGROUND
Studies have confirmed the salutary effects of progesterone (P4) on traumatic brain injury (TBI). This study investigated the beneficial effects of P4 via its receptors on TBI, and also whether progesterone receptors (PRs) can modulate TBI through PI3K/Akt pathway.
MATERIAL AND METHODS
Marmarou method was utilized to induce diffuse TBI in ovariectomized rats. P4 (1.7 mg/kg) or the vehicle (oil) was administered 30 min after TBI induction. Moreover, RU486 (PR antagonist) and its vehicle (DMSO) were injected before TBI induction and P4 injection. Brain Evans blue content, brain water content (WC), various oxidative stress parameters, IL-1β levels, tumor necrosis factor-α (TNF-α), histopathological alterations, and also phosphorylated Akt (p-Akt) and PI3K expressions in the brain were assessed 24 h after TBI. The veterinary comma scale (VCS) was measured before and after TBI at different times.
RESULTS
The findings revealed that P4 caused an increase in VCS and a decrease in brain WC, oxidative stress, TNF-α and IL-1β levels. RU486 inhibited the beneficial effects of P4 on these indices. Moreover, RU486 prevented the reduction of brain edema, inflammation, and apoptosis caused by P4. Moreover, P4 following TBI increased the expression of PI3K/p-Akt protein in the brain. RU486 eliminated the effects of P4 on PI3K/p-Akt expression.
CONCLUSION
According to these findings, PRs are acting as critical mediators for the neuroprotective properties of P4 on oxidative stress, pro-inflammatory cytokine levels, and neurological outcomes. PRs also play an important role in regulating the PI3K/p-Akt expression and nongenomic function of P4.
Topics: Rats; Animals; Proto-Oncogene Proteins c-akt; Receptors, Progesterone; Phosphatidylinositol 3-Kinases; Neuroprotective Agents; Tumor Necrosis Factor-alpha; Mifepristone; Brain Injuries, Traumatic; Progesterone
PubMed: 37661235
DOI: 10.1002/brb3.3244 -
The Lancet. Oncology Sep 2023The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of... (Randomized Controlled Trial)
Randomized Controlled Trial
Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study.
BACKGROUND
The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer.
METHODS
In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a-c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and baseline Ki67 score of at least 5%. The study was conducted at 59 hospital or clinic sites in 11 countries globally. Participants were randomly assigned (1:1) to giredestrant 30 mg oral daily or anastrozole 1 mg oral daily on days 1-14 (window-of-opportunity phase) via an interactive web-based system with permuted-block randomisation with block size of four. Randomisation was stratified by cT stage, baseline Ki67 score, and progesterone receptor status. A 16-week neoadjuvant phase comprised the same regimen plus palbociclib 125 mg oral daily on days 1-21 of a 28-day cycle, for four cycles. The primary endpoint was geometric mean relative Ki67 score change from baseline to week 2 in patients with complete central Ki67 scores at baseline and week 2 (window-of-opportunity phase). Safety was assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov (NCT04436744) and is complete.
FINDINGS
Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0-68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0-67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was -75% (95% CI -80 to -70) with giredestrant and -67% (-73 to -59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3-4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction).
INTERPRETATION
Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials.
FUNDING
F Hoffmann-La Roche.
Topics: Humans; Female; Middle Aged; Anastrozole; Breast Neoplasms; Receptors, Estrogen; Neoadjuvant Therapy; Ki-67 Antigen
PubMed: 37657462
DOI: 10.1016/S1470-2045(23)00268-1 -
BMC Pregnancy and Childbirth Aug 2023To evaluate the effect of basal luteinizing hormone (bLH) levels on In Vitro Fertilization/Intra-Cytoplasmic Injections (IVF/ICSI) outcomes in polycystic ovary syndrome...
OBJECTIVE
To evaluate the effect of basal luteinizing hormone (bLH) levels on In Vitro Fertilization/Intra-Cytoplasmic Injections (IVF/ICSI) outcomes in polycystic ovary syndrome (PCOS).
METHODS
A total of 256 PCOS patients who underwent IVF/ICSI treatment in our center from January 2018 to January 2022 were analyzed retrospectively. The patients were based on the third quartile (12.455) of the basal LH value was taken as the cut-off value and was divided into high and low LH group: high LH group (LH ≥ 12.455 IU / L) and low LH group (LH < 12.455 IU / L) and the OC group was pretreated with oral contraceptives. The outcomes in ovulation induction and embryo transfer cycles of the three groups were then compared. In addition, factors influencing the number of good quality embryos and the early onset LH peak were analyzed.
RESULTS
Ages, infertility duration, body mass index (BMI), and basal follicle-stimulating hormone (FSH), and progesterone (P), testosterone (T) levels were not significantly different among the three groups (p > 0.05). However,there were significant differences in basal LH and basal E2 between low LH group and high LH group, and there were significant differences in basal LH between high LH group and OC group (p < 0.05). LH on the antagonist day was significantly different between low LH group and high LH group and between high LH group and OC group (p < 0.05). LH on the hCG (human Chorionic Gonadotropin) day there were significant differences between low LH group and OC group, high LH group and OC group (p < 0.05). The Mode of triggering between the three groups had significant differences between the two groups (p < 0.05). In addition, the number of days from gonadotropin (Gn) initiation to antagonist addition were significantly different among the three groups (p < 0.05). In addition, total Gn doses,the number of oocytes retrieved, the number of Gn days, 2pronucleus (2PN) numbers, number of good quality embryos, and number of high risk OHSS (Ovarian Hyper-stimulation Syndrome), cases with OHSS occurrences were not significantly different among the three groups (p > 0.05). Moreover, the cycle and clinical pregnancy outcomes and the cumulative clinical pregnancy rate and the cumulative live birth rate were not significantly different among the three groups (p > 0.05). LH levels on the day of antagonist addition affected the number of good-quality embryos (B < 0, p < 0.05). However, LH levels on the day antagonist was added were not significantly correlated with basal LH levels (Pearson correlation coefficient = 0.259), the ROC curve was constructed for the logistic prediction model of the early onset LH peak, and the AUC value was 0.747, indicating that the logistic combined model we constructed had a good ability to predict the early onset LH peak.
CONCLUSION
Basal LH levels do not affect the pregnancy outcomes in PCOS patients after antagonist protocols. Besides, LH levels on the day of antagonist addition affect the number of good quality embryos for PCOS patients undergoing IVF /ICSI.
Topics: Female; Pregnancy; Humans; Polycystic Ovary Syndrome; Retrospective Studies; Sperm Injections, Intracytoplasmic; Fertilization in Vitro; Infertility
PubMed: 37644399
DOI: 10.1186/s12884-023-05944-4 -
Proceedings of the National Academy of... Aug 2023Glucocorticoids (GC) are potent anti-inflammatory agents, broadly used to treat acute and chronic inflammatory diseases, e.g., critically ill COVID-19 patients or...
Glucocorticoids (GC) are potent anti-inflammatory agents, broadly used to treat acute and chronic inflammatory diseases, e.g., critically ill COVID-19 patients or patients with chronic inflammatory bowel diseases. GC not only limit inflammation but also promote its resolution although the underlying mechanisms are obscure. Here, we reveal reciprocal regulation of 15-lipoxygenase (LOX) isoform expression in human monocyte/macrophage lineages by GC with respective consequences for the biosynthesis of specialized proresolving mediators (SPM) and their 15-LOX-derived monohydroxylated precursors (mono-15-OH). Dexamethasone robustly up-regulated pre-mRNA, mRNA, and protein levels of ALOX15B/15-LOX-2 in blood monocyte-derived macrophage (MDM) phenotypes, causing elevated SPM and mono-15-OH production in inflammatory cell types. In sharp contrast, dexamethasone blocked ALOX15/15-LOX-1 expression and impaired SPM formation in proresolving M2-MDM. These dexamethasone actions were mimicked by prednisolone and hydrocortisone but not by progesterone, and they were counteracted by the GC receptor (GR) antagonist RU486. Chromatin immunoprecipitation (ChIP) assays revealed robust GR recruitment to a putative enhancer region within intron 3 of the ALOX15B gene but not to the transcription start site. Knockdown of 15-LOX-2 in M1-MDM abolished GC-induced SPM formation and mono-15-OH production. Finally, ALOX15B/15-LOX-2 upregulation was evident in human monocytes from patients with GC-treated COVID-19 or patients with IBD. Our findings may explain the proresolving GC actions and offer opportunities for optimizing GC pharmacotherapy and proresolving mediator production.
Topics: Humans; Glucocorticoids; Arachidonate 15-Lipoxygenase; COVID-19; Inflammation; Dexamethasone; Lipids
PubMed: 37603745
DOI: 10.1073/pnas.2302070120 -
Cancers Jul 2023The expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer cells is critical for... (Review)
Review
The expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer cells is critical for determining tumor aggressiveness and targeting therapies. The presence of such receptors allows for the use of antagonists that effectively reduce breast cancer growth and dissemination. However, the absence of such receptors in triple-negative breast cancer (TNBC) reduces the possibility of targeted therapy, making these tumors very aggressive with a poor outcome. Cancers are not solely composed of tumor cells, but also include several types of infiltrating cells, such as fibroblasts, macrophages, and other immune cells that have critical functions in regulating cancer cell behaviors. In addition to these cells, the extracellular matrix (ECM) has become an important player in many aspects of breast cancer biology, including cell growth, motility, metabolism, and chemoresistance. Hyaluronan (HA) is a key ECM component that promotes cell proliferation and migration in several malignancies. Notably, HA accumulation in the tumor stroma is a negative prognostic factor in breast cancer. HA metabolism depends on the fine balance between HA synthesis by HA synthases and degradation yielded by hyaluronidases. All the different cell types present in the tumor can release HA in the ECM, and in this review, we will describe the role of HA and HA metabolism in different breast cancer subtypes.
PubMed: 37568628
DOI: 10.3390/cancers15153813 -
BioMed Research International 2023During the frozen-thawed embryo transfer (FET) method, controlled ovarian hyperstimulation is used. At the same time, progesterone support is given for luteal phase...
PURPOSE
During the frozen-thawed embryo transfer (FET) method, controlled ovarian hyperstimulation is used. At the same time, progesterone support is given for luteal phase support. In this study, we investigated the effects of various luteal phase support agents administered orally, intramuscularly (IM), and vaginally during FET on pregnancy rates.
METHODS
The files of 166 patients between the ages of 21 and 44 in the Assisted Reproductive Techniques Center of Acıbadem Mehmet Ali Aydınlar University Atakent Hospital were analyzed retrospectively between 2016 and 2022. The patients' FSH, LH, E2, P4, AMH, and TSH levels were measured. The GnRH antagonist protocol was initiated on the 2nd or 3rd day of menstruation. Three types of progesterone agents were used in females with PCOS. Three different methods were applied: 50 mg/ml of IM progesterone daily, 90 mg of progesterone gel 2∗1 vaginally, and dydrogesterone acetate tb. orally 3∗1. FET was performed on women who received 21 days of treatment by thawing 5th-day embryos. B-hCG was performed on the 12th day after the transfer, and evaluations were made. The study results were evaluated as follows: for the whole study group, for those <30 years of age, for those 30-35 years of age, and for those >35 years of age.
RESULTS
A total of 164 patients, 57 females using vaginal progesterone gel, 30 females using oral progesterone tablet, and 77 females using IM progesterone, who met the inclusion criteria, were included in the study. The pregnancy outcomes of IM progesterone application were statistically significantly higher in the entire study group and the >35 age group when compared to the vaginal progesterone gel application. It was found that the pregnancy outcomes of IM progesterone application increased statistically significantly in the <30 age group when compared to outcomes in the other groups, using vaginal progesterone gel and oral progesterone tb.
CONCLUSIONS
We found that IM progesterone application was more effective than vaginal progesterone gel application for luteal phase support. Many randomized controlled, especially live birth rate studies, are required before results can more closely approximate those for the general population.
Topics: Pregnancy; Humans; Female; Young Adult; Adult; Pregnancy Outcome; Progesterone; Retrospective Studies; Luteal Phase; Embryo Transfer; Pregnancy Rate
PubMed: 37529251
DOI: 10.1155/2023/8157210