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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 -
Frontiers in Pharmacology 2023Endometriosis is one of the most common benign gynecological disorders in reproductive-aged women. The major symptoms are chronic pelvic pain and infertility. Despite... (Review)
Review
Endometriosis is one of the most common benign gynecological disorders in reproductive-aged women. The major symptoms are chronic pelvic pain and infertility. Despite its profound impact on women's health and quality of life, its pathogenesis has not been fully elucidated, it cannot be cured and the long-term use of drugs yields severe side effects and hinders fertility. This review aims to present the advances in pathogenesis and the newly reported lead compounds and drugs managing endometriosis. This paper investigated Genetic changes, estrogen-dependent inflammation induction, progesterone resistance, imbalance in proliferation and apoptosis, angiogenesis, lymphangiogenesis and neurogenesis, and tissue remodeling in its pathogenesis; and explored the pharmacological mechanisms, constitutive relationships, and application prospects of each compound in the text. To date, Resveratrol, Bay1316957, and bardoxifene were effective against lesions and pain in controlled animal studies. In clinical trials, Quinagolide showed no statistical difference with the placebo group; the results of phase II clinical trial of the IL-33 antibody have not been announced yet; clinical trial stage III of vilaprisan was suspended due to drug toxicity. Elagolix was approved for the treatment of endometriosis-related pain, but clinical studies of Elagolix for the pretreatment of patients with endometriosis to before In vitro fertilization treatment have not been fulfilled. The results of a clinical study of Linzagolix in patients with moderate to severe endometriosis-related pain have not been disclosed yet. Letrozole improved the fertility of patients with mild endometriosis. For endometriosis patients with infertility, oral GnRH antagonists and aromatase inhibitors are promising drugs, especially Elagolix and Letrozole.
PubMed: 37416064
DOI: 10.3389/fphar.2023.1199010 -
Heliyon Jul 2023Although numerous studies have investigated the potential correlation between follicular fluid (FF) steroid concentrations and fertilization/intracytoplasmic sperm...
BACKGROUND
Although numerous studies have investigated the potential correlation between follicular fluid (FF) steroid concentrations and fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes, few have accounted for the effect of controlled ovarian hyperstimulation regimes on FF steroid concentrations.
OBJECTIVE
To comprehensively compare follicular steroid concentrations between women stimulated with gonadotropin-releasing hormone agonist (GnRHa) and antagonist (GnRHant) protocols and to explore the associations between FF steroid concentrations and IVF/ICSI outcomes.
METHODS
A total of 295 infertile women undergoing IVF/ICSI from January 2018 to May 2020 were enrolled. Eighty-four and 211 women received GnRHa and GnRHant protocols, respectively. Seventeen steroids in FF were quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS), and the correlation of follicular steroids with clinical pregnancy was explored.
RESULTS
Follicular steroid concentrations were similar between the GnRHa and GnRHant groups. Follicular cortisone levels were adversely associated with clinical pregnancy in fresh embryo transfers. Receiver operating characteristic (ROC) analysis revealed an area under the ROC curve (AUC) of 0.639 (95% confidence interval = 0.527-0.751, = 0.025) for predicting non-pregnancy, with an optimal cutoff value of 15.81 ng/mL (sensitivity = 33.3%, specificity = 94.1%). Women with FF cortisone concentrations ≥15.81 ng/mL were fifty times less likely to achieve clinical pregnancy in fresh embryo transfers than those with FF cortisone levels below this threshold (adjusted OR = 0.019, 95% confidence interval = 0.002-0.207, = 0.001) after adjusting for age, body mass index, baseline serum progesterone levels, serum levels of luteinizing hormone, estradiol and progesterone on human chorionic gonadotropin day, ovarian stimulation protocols, and the number of transferred embryos.
CONCLUSIONS
There was no significant difference in intrafollicular steroid levels between GnRHa and GnRHant protocols, and intrafollicular cortisone level ≥15.81 ng/mL was found to be a strong negative predictor of clinical pregnancy in fresh embryo transfers with high specificity.
PubMed: 37415947
DOI: 10.1016/j.heliyon.2023.e17492 -
Frontiers in Endocrinology 2023To investigate the impact of the progesterone concentration on the human chorionic gonadotropin (hCG) trigger day on clinical outcomes with an antagonist protocol.
Impact of progesterone concentration on human chorionic gonadotropin trigger day on clinical outcomes with one top-quality cleavage-stage embryo or blastocyst transfer in fresh fertilization cycles.
OBJECTIVE
To investigate the impact of the progesterone concentration on the human chorionic gonadotropin (hCG) trigger day on clinical outcomes with an antagonist protocol.
METHODS
The retrospective cohort study included a total of 1,550 fresh autologous ART cycles with one top-quality embryo transfer. Multivariate regression analysis, curve fitting, and threshold effect analysis were performed.
RESULTS
A significant association was found between the progesterone concentration and clinical pregnancy rate (adjusted OR, 0.77; 95% CI, 0.62-0.97; P = 0.0234), especially in blastocyst transfer (adjusted OR, 0.56; 95% CI, 0.39-0.78; P = 0.0008). The association between the progesterone concentration and the ongoing pregnancy rate was insignificant. The clinical pregnancy rate showed a linear relationship with an increased progesterone concentration in cleavage-stage embryo transfer. In blastocyst transfer, as the progesterone concentration increased, the clinical and ongoing pregnancy rates showed a parabolic reverse-U curve; the curve initially increased before declining at high progesterone concentrations. The clinical pregnancy rate increased with a progesterone concentration up to 0.80 ng/mL rather than tended to be stable. The clinical pregnancy rate significantly decreased when the progesterone concentration was ≥0.80 ng/mL.
CONCLUSION
The progesterone concentration on the hCG trigger day exhibits a curvilinear relationship with pregnancy outcomes in blastocyst transfer cycles, and the optimal threshold of the progesterone concentration is 0.80 ng/mL.
Topics: Pregnancy; Female; Humans; Progesterone; Retrospective Studies; Fertilization in Vitro; Embryo Transfer; Chorionic Gonadotropin
PubMed: 37409225
DOI: 10.3389/fendo.2023.1085287 -
Endocrinology Jun 2023Progesterone serum levels have been identified as a potential predictor for treatment effect in men with advanced prostate cancer, which is an androgen-driven disease....
Progesterone serum levels have been identified as a potential predictor for treatment effect in men with advanced prostate cancer, which is an androgen-driven disease. Although progesterone is the most abundant sex steroid in orchiectomized (ORX) male mice, the origins of progesterone in males are unclear. To determine the origins of progesterone and androgens, we first determined the effect of ORX, adrenalectomy (ADX), or both (ORX + ADX) on progesterone levels in multiple male mouse tissues. As expected, intratissue androgen levels were mainly testicular derived. Interestingly, progesterone levels remained high after ORX and ORX + ADX with the highest levels in white adipose tissue and in the gastrointestinal tract. High progesterone levels were observed in mouse chow and exceptionally high progesterone levels were observed in food items such as dairy, eggs, and beef, all derived from female animals of reproductive age. To determine if orally ingested progesterone contributes to tissue levels of progesterone in males, we treated ORX + ADX and sham mice with isotope-labeled progesterone or vehicle by oral gavage. We observed a significant uptake of labeled progesterone in white adipose tissue and prostate, suggesting that dietary progesterone may contribute to tissue levels of progesterone. In conclusion, although adrenal-derived progesterone contributes to intratissue progesterone levels in males, nonadrenal progesterone sources also contribute. We propose that dietary progesterone is absorbed and contributes to intratissue progesterone levels in male mice. We speculate that food with high progesterone content could be a significant source of progesterone in males, possibly with consequences for men undergoing androgen deprivation therapy for prostate cancer.
Topics: Humans; Cattle; Mice; Male; Animals; Androgens; Progesterone; Androgen Antagonists; Prostatic Neoplasms; Adrenalectomy; Orchiectomy
PubMed: 37403231
DOI: 10.1210/endocr/bqad103 -
F&S Reports Jun 2023Evaluate the efficacy and safety of elagolix, a GnRH antagonist, to treat polycystic ovarian syndrome (PCOS).
OBJECTIVE
Evaluate the efficacy and safety of elagolix, a GnRH antagonist, to treat polycystic ovarian syndrome (PCOS).
DESIGN
A phase 2, multicenter, double-blind, randomized, placebo-controlled trial.
SETTING
Outpatient and academic medical centers.
PATIENTS
One hundred fourteen women with PCOS (aged 18-35 years, body mass index 18.5-38 kg/m).
INTERVENTIONS
Patients were randomized 2:2:2:2:2:3 to elagolix (25 mg twice daily, 50 mg once daily, 75 mg twice daily, 150 mg once daily, and 300 mg twice daily) or placebo.
MAIN OUTCOME MEASURES
The primary endpoint was menstrual cycle normalization (defined as 2 menstrual cycles 21-35 days in length during the 4-month treatment period). The secondary endpoint was change from baseline to week 1 in the area under the luteinizing hormone (LH) serum concentration-time curve (AUC). Additional endpoints included change from baseline in serum hormone levels.
RESULTS
No significant improvement in restoring normal menstrual cycles was observed in treated subjects; 3 of 114 patients met the primary endpoint. Six patients experienced progesterone elevations indicative of ovulation. The LH levels decreased from baseline to week 16, and LH AUC was significantly reduced from baseline to week 1 in all elagolix treatment groups (<.1 vs placebo). Follicle-stimulating hormone (FSH) levels generally remained stable through week 16, with no significant differences in FSH AUCs. Serum estradiol and testosterone concentrations were consistently reduced from baseline in all elagolix dose groups compared with placebo. Adverse event rates were similar across treatment groups.
CONCLUSIONS
Elagolix treatment did not normalize the ovulatory cycle in patients with PCOS.
CLINICAL TRIAL REGISTRATION NUMBER
NCT03951077.
PubMed: 37398623
DOI: 10.1016/j.xfre.2023.02.007 -
F&S Reports Jun 2023To study the clinical use of elagolix in ovarian stimulation and its effect on premature ovulation in a cohort of women undergoing oocyte donation.
OBJECTIVE
To study the clinical use of elagolix in ovarian stimulation and its effect on premature ovulation in a cohort of women undergoing oocyte donation.
DESIGN
A prospective cohort study with the use of historical controls.
SETTING
A private reproductive endocrinology and infertility clinic.
PATIENTS
Seventy-five oocyte donors and 75 historical donors, aged 21-30 years, who had each passed Food and Drug Administration and American Society for Reproductive Medicine-approved oocyte donor screening.
INTERVENTIONS
Administration of elagolix 200 mg orally every night at bedtime with development of a follicular size of ≥14 mm for ovulation suppression compared with ganirelix 250 μg every night at bedtime.
MAIN OUTCOME MEASURES
Premature ovulation rate, total oocytes, mature oocytes, maximum estradiol, luteinizing hormone, and progesterone levels.
RESULTS
Oocytes were available in all retrievals because there were no instances of premature ovulation in either the elagolix or ganirelix groups. There were no statistically significant differences between the groups in baseline demographics. Both groups had the same amounts of gonadotropins consumed and days of stimulation. The average number of total oocytes was similar between the control group and elagolix group (30.55 vs. 30.31). Furthermore, the average number of mature oocytes was similar between the control and study groups (25.42 vs. 24.73). An analysis of the 580 fresh oocytes in the elagolix group and the 737 fresh oocytes in the ganirelix group showed similar outcomes with fertilization rates of 79.7% and 84.6%, respectively. Blastocyst development rates were also similar: 62.9% in the elagolix group and 57.3% in the ganirelix group.
CONCLUSIONS
Compared with a historical control group using ganirelix, patients receiving elagolix demonstrated a similar number of oocytes and mature oocytes with on average 4.2 fewer injections per cycle and average per-cycle patient savings of $289.10.
CLINICAL TRIAL REGISTRATION NUMBER
Western IRB Pr. No.: 20191163, April 11, 2019. First enrollment June 20, 2019.
PubMed: 37398618
DOI: 10.1016/j.xfre.2023.03.006 -
Frontiers in Endocrinology 2023Anti-Mullerian hormone (AMH) has been recently identified as a potential predictor of live birth rates (LBRs) following assisted reproductive technology (ART) treatment....
High anti-Mullerian hormone level is adversely associated with cumulative live birth rates of two embryo transfers after the first initiated cycle in patients with polycystic ovary syndrome.
OBJECTIVE
Anti-Mullerian hormone (AMH) has been recently identified as a potential predictor of live birth rates (LBRs) following assisted reproductive technology (ART) treatment. This study aimed to investigate the association between AMH levels and the outcomes of fertilization (IVF) in patients with polycystic ovary syndrome (PCOS).
METHODS
Patients with PCOS initiating their first ovarian stimulation under the gonadotropin-releasing hormone antagonist protocol at the Guangdong Women and Children Hospital, China, were enrolled from November 2014 to September 2018. A total of 157 patients who underwent fresh embryo transfer (ET) cycles were included in group A, whereas 187 patients who underwent frozen-thawed ET cycles were included in group B. After the failure of the first ET cycle, 94 patients underwent the second ET cycle with frozen-thawed embryos. Of these 94 patients, 52 had failed the first fresh ET cycle (group C) and 42 had failed the first frozen-thawed ET cycle (group D). Successful embryo transfer was defined as live birth. This retrospective cohort study addressed the association between AMH levels and pregnancy outcomes using logistic regression approaches. After adjusting for age, body mass index, antral follicle counts, baseline follicle-stimulating hormone levels and baseline progesterone levels, LBRs were compared among the four groups and the cumulative live birth rate after two embryo transfers (TCLBR) was calculated.
RESULTS
The LBRs showed no differences among the four groups. Higher serum AMH levels were found to be associated with a lower TCLBR [adjusted OR 0.937 (0.888-0.987), ]. In patients who underwent the second ET cycle, LBRs were inversely proportional to AMH levels [crude OR 0.904 (0.828-0.986), versus adjusted OR 0.845 (0.754-0.946), , respectively]. In addition, the LBR was approximately 61%-78% lower in the group with AMH levels of >12 ng/mL [crude OR 0.391 (0.168-0.912), versus adjusted OR 0.217 (0.074-0.635), , respectively].
CONCLUSIONS
Among PCOS patients high AMH level (>12 ng/ml) is found to be associated with low TCLBR and low LBR of the second embryo transfer cycles. The results provide limited clinical inferences and warrant further investigation.
Topics: Child; Pregnancy; Humans; Female; Anti-Mullerian Hormone; Polycystic Ovary Syndrome; Birth Rate; Retrospective Studies; Embryo Transfer; Peptide Hormones
PubMed: 37388214
DOI: 10.3389/fendo.2023.1123125