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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 -
Journal of Ovarian Research Jun 2023A premature luteinizing hormone (LH) surge refers to an endogenous LH peak that occurs before follicle maturation or human chorionic gonadotropin injection in the...
A premature luteinizing hormone surge without elevated progesterone levels has no adverse effect on cumulative live birth rate in patient undergoing a flexible GnRH antagonist protocol: a retrospective study.
BACKGROUND
A premature luteinizing hormone (LH) surge refers to an endogenous LH peak that occurs before follicle maturation or human chorionic gonadotropin injection in the process of controlled ovarian hyperstimulation. The effect of premature LH surge on pregnancy outcomes in fresh embryo transfer cycles is still controversial. The aim of this study was to explore the effect of a premature LH surge without elevated progesterone levels on the cumulative pregnancy rate (CPR) and cumulative live birth rate (CLBR) of patients during a flexible GnRH antagonist protocol.
METHODS
A total of 730 infertile women undergoing IVF/ICSI were recruited for this retrospective study. Only women who either delivered a live infant or had no remaining frozen embryos after a single stimulation cycle were included in the analysis. During the study period, each patient underwent a flexible GnRH antagonist protocol. Women were divided into two groups according to the presence or absence of a premature LH surge. The primary outcome measures were the CPR and CLBR per ovarian stimulation cycle. The secondary outcome measures were the number of oocytes retrieved, fertilization rate, good-quality embryo rate, and clinical pregnancy rate.
RESULTS
Ninety-one women (12.47%) experienced a premature LH surge without elevated progesterone levels, and the other 639 (87.53%) women were assigned to the control group. The numbers of oocytes retrieved and fertilization rate were significantly greater in the premature LH surge group than in the control group. There was no significant difference between groups in the good-quality embryo rate, clinical pregnancy rate or live birth rate in the fresh embryo transfer cycle. The primary outcome measures, the CPR and CLBR per ovarian stimulation cycle, were not significantly different between the premature LH surge group and the control group. According to the analysis stratified by ovarian response (normal or high), there were no significant differences in pregnancy outcomes between the groups with and without a premature LH surge.
CONCLUSIONS
The retrospective study demonstrated that the patients experiencing a transient premature LH surge without progesterone elevation had equivalent pregnancy outcomes with those without a premature LH surge on a flexible GnRH antagonist protocol. The present conclusions need to be further validated in a prospective well-designed large-scale study.
Topics: Female; Humans; Pregnancy; Birth Rate; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Hormone Antagonists; Infertility, Female; Luteinizing Hormone; Ovulation Induction; Pregnancy Rate; Progesterone; Prospective Studies; Retrospective Studies
PubMed: 37370146
DOI: 10.1186/s13048-023-01219-w -
Frontiers in Oncology 2023The bibliometric analysis aims to identify research trends in estrogen receptor (ERs) and progesterone receptor (PRs) in prostate cancer (PCa), and also discuss the...
INTRODUCTION
The bibliometric analysis aims to identify research trends in estrogen receptor (ERs) and progesterone receptor (PRs) in prostate cancer (PCa), and also discuss the hotspots and directions of this field.
METHODS
835 publications were sourced from the Web of Science database (WOS) from 2003 to 2022. Citespace, VOSviewer, and Bibliometrix were used for the bibliometric analysis.
RESULTS
The number of published publications increased in early years, but declined in the last 5 years. The United States was the leading country in citations, publications, and top institutions. Prostate and Karolinska Institutet were the most publications of journal and institution, respectively. Jan-Ake Gustafsson was the most influential author based on the number of citations/publications. The most cited paper was "Estrogen receptors and human disease" by Deroo BJ, published in the Journal of Clinical Investigation. The most frequently used keywords were PCa (n = 499), gene-expression (n = 291), androgen receptor (AR) (n = 263), and ER (n = 341), while ERb (n = 219) and ERa (n = 215) further emphasized the importance of ER.
CONCLUSIONS
This study provides useful guidance that ERa antagonists, ERb agonists, and the combination of estrogen with androgen deprivation therapy (ADT) will potentially serve as a new treatment strategy for PCa. Another interesting topic is relationships between PCa and the function and mechanism of action of PRs subtypes. The outcome will assist scholars in gaining a comprehensive understanding of the current status and trends in the field, and provide inspiration for future research.
PubMed: 37361598
DOI: 10.3389/fonc.2023.1111296 -
Journal For Immunotherapy of Cancer Jun 2023Progress in breast cancer (BC) research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best studied...
BACKGROUND
Progress in breast cancer (BC) research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best studied mouse strain, C57BL/6, is also the only one for which multiple genetic variants are available to facilitate the exploration of the cancer-immunity dialog. Driven by the fact that no hormone receptor-positive (HR) C57BL/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines.
METHODS
BC was induced in female C57BL/6 mice using a synthetic progesterone analog (medroxyprogesterone acetate, MPA) combined with a DNA damaging agent (7,12-dimethylbenz[a]anthracene, DMBA). Cell lines were established from these tumors and selected for dual (estrogen+progesterone) receptor positivity, as well as transplantability into C57BL/6 immunocompetent females.
RESULTS
One cell line, which we called B6BC, fulfilled these criteria and allowed for the establishment of invasive estrogen receptor-positive (ER) tumors with features of epithelial to mesenchymal transition that were abundantly infiltrated by myeloid immune populations but scarcely by T lymphocytes, as determined by single-nucleus RNA sequencing and high-dimensional leukocyte profiling. Such tumors failed to respond to programmed cell death-1 (PD-1) blockade, but reduced their growth on treatment with ER antagonists, as well as with anthracycline-based chemotherapy, which was not influenced by T-cell depletion. Moreover, B6BC-derived tumors reduced their growth on CD11b blockade, indicating tumor sustainment by myeloid cells. The immune environment and treatment responses recapitulated by B6BC-derived tumors diverged from those of ER TS/A cell-derived tumors in BALB/C mice, and of ER E0771 cell-derived and MPA/DMBA-induced tumors in C57BL/6 mice.
CONCLUSIONS
B6BC is the first transplantable HR BC cell line derived from C57BL/6 mice and B6BC-derived tumors recapitulate the complex tumor microenvironment of locally advanced HR BC naturally resistant to PD-1 immunotherapy.
Topics: Mice; Female; Animals; Progesterone; Epithelial-Mesenchymal Transition; Mice, Inbred BALB C; Mice, Inbred C57BL; Cell Line, Tumor; Carcinoma; Tumor Microenvironment
PubMed: 37344100
DOI: 10.1136/jitc-2023-007117 -
European Journal of Endocrinology Jul 2023Aldo-keto reductase 1C3 (AKR1C3) has been postulated to be involved in androgen, progesterone, and estrogen metabolism. Aldo-keto reductase 1C3 inhibition has been... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Aldo-keto reductase 1C3 (AKR1C3) has been postulated to be involved in androgen, progesterone, and estrogen metabolism. Aldo-keto reductase 1C3 inhibition has been proposed for treatment of endometriosis and polycystic ovary syndrome. Clinical biomarkers of target engagement, which can greatly facilitate drug development, have not yet been described for AKR1C3 inhibitors. Here, we analyzed pharmacodynamic data from a phase 1 study with a new selective AKR1C3 inhibitor, BAY1128688, to identify response biomarkers and assess effects on ovarian function.
DESIGN
In a multiple-ascending-dose placebo-controlled study, 33 postmenopausal women received BAY1128688 (3, 30, or 90 mg once daily or 60 mg twice daily) or placebo for 14 days. Eighteen premenopausal women received 60 mg BAY1128688 once or twice daily for 28 days.
METHODS
We measured 17 serum steroids by liquid chromatography-tandem mass spectrometry, alongside analysis of pharmacokinetics, menstrual cyclicity, and safety parameters.
RESULTS
In both study populations, we observed substantial, dose-dependent increases in circulating concentrations of the inactive androgen metabolite androsterone and minor increases in circulating etiocholanolone and dihydrotestosterone concentrations. In premenopausal women, androsterone concentrations increased 2.95-fold on average (95% confidence interval: 0.35-3.55) during once- or twice-daily treatment. Note, no concomitant changes in serum 17β-estradiol and progesterone were observed, and menstrual cyclicity and ovarian function were not altered by the treatment.
CONCLUSIONS
Serum androsterone was identified as a robust response biomarker for AKR1C3 inhibitor treatment in women. Aldo-keto reductase 1C3 inhibitor administration for 4 weeks did not affect ovarian function.ClinicalTrials.gov Identifier: NCT02434640; EudraCT Number: 2014-005298-36.
Topics: Female; Humans; Aldo-Keto Reductase Family 1 Member C3; Androgens; Androsterone; Dihydrotestosterone; Hydroxyprostaglandin Dehydrogenases; Progesterone; Steroids
PubMed: 37306288
DOI: 10.1093/ejendo/lvad063 -
Molecules (Basel, Switzerland) May 2023Steroid hormones are the key regulators of inflammatory and autoimmune processes. The role of steroid hormones is mostly inhibitory in these processes. The expression of...
Steroid hormones are the key regulators of inflammatory and autoimmune processes. The role of steroid hormones is mostly inhibitory in these processes. The expression of IL-6, TNFα, and IL-1β, as markers of inflammation, and TGFβ, as a marker of fibrosis, could be useful tools to predict the response of an individual's immune system to the different progestins suitable for the treatment of menopausal inflammatory disorders, including endometriosis. In this study, the progestins P4 and MPA, as well as the novel progestin gestobutanoyl (GB), which possess potent anti-inflammatory properties towards endometriosis, were studied at a fixed concentration of 10 µM. Their influence on the production of the above cytokines in PHA-stimulated peripheral blood mononuclear cells (PBMCs) during 24 h incubation was evaluated by ELISA. It was found that synthetic progestins stimulated the production of IL-1β, IL-6, and TNFα and inhibited TGFβ production, while P4 inhibited IL-6 (33% inhibition) and did not influence TGFβ production. In the MTT-viability test, P4 also decreased PHA-stimulated PBMC viability by 28% during 24 h incubation, but MPA and GB did not have any inhibitory or stimulatory effects. The luminol-dependent chemiluminescence (LDC) assay revealed the anti-inflammatory and antioxidant properties of all the tested progestins, as well as some other steroid hormones and their antagonists: cortisol, dexamethasone, testosterone, estradiol, cyproterone, and tamoxifen. Of these, tamoxifen showed the most pronounced effect on the oxidation capacity of PBMC but not on that of dexamethasone, as was expected. Collectively, these data demonstrate that PBMCs from menopausal women respond differently to P4 and synthetic progestins, most likely due to distinct actions via various steroid receptors. It is not only the progestin affinity to nuclear progesterone receptors (PR), androgen receptors, glucocorticoid receptors, or estrogen receptors that is important for the immune response, but also the membrane PR or other nongenomic structures in immune cells.
Topics: Female; Humans; Progestins; Tumor Necrosis Factor-alpha; Leukocytes, Mononuclear; Luminol; Endometriosis; Interleukin-6; Luminescence; Progesterone; Receptors, Progesterone; Cytokines; Progesterone Congeners; Receptors, Androgen; Menopause; Tamoxifen; Transforming Growth Factor beta; Dexamethasone
PubMed: 37298830
DOI: 10.3390/molecules28114354 -
Clinical Cancer Research : An Official... Aug 2023GDC-0927 is a novel, potent, nonsteroidal, orally bioavailable, selective estrogen receptor (ER) degrader that induces tumor regression in ER+ breast cancer xenograft...
PURPOSE
GDC-0927 is a novel, potent, nonsteroidal, orally bioavailable, selective estrogen receptor (ER) degrader that induces tumor regression in ER+ breast cancer xenograft models.
PATIENTS AND METHODS
This phase I dose-escalation multicenter study enrolled postmenopausal women with ER+/HER2- metastatic breast cancer to determine the safety, pharmacokinetics, and recommended phase II dose of GDC-0927. Pharmacodynamics was assessed with [18F]-fluoroestradiol (FES) PET scans.
RESULTS
Forty-two patients received GDC-0927 once daily. The MTD was not reached. The most common adverse events (AE) regardless of causality were nausea, constipation, diarrhea, arthralgia, fatigue, hot flush, back pain, and vomiting. There were no deaths, grade 4/5 AEs, or treatment-related serious AEs. Two patients experienced grade 2 AEs of special interest of deep vein thrombosis and jugular vein thrombosis, both considered unrelated to GDC-0927. Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by >90% reduction in FES uptake and an approximately 40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease. Baseline levels of ER and progesterone receptor protein and mutant ESR1 circulating tumor DNA did not correlate with clinical benefit.
CONCLUSIONS
GDC-0927 appeared to be well tolerated with pharmacokinetics supporting once-daily dosing. There was evidence of target engagement and preliminary evidence of antitumor activity in heavily pretreated patients with advanced/metastatic ER+/HER2- breast cancer with and without ESR1 mutations.
Topics: Humans; Female; Breast Neoplasms; Receptors, Estrogen; Postmenopause; Estrogen Receptor Antagonists; Positron-Emission Tomography
PubMed: 37261814
DOI: 10.1158/1078-0432.CCR-23-0011 -
Ginekologia Polska May 2023to investigate the possibility of using the ratio of serum progesterone level to the number of follicles, according to ovarian response in the day of human chorionic...
OBJECTIVES
to investigate the possibility of using the ratio of serum progesterone level to the number of follicles, according to ovarian response in the day of human chorionic gonadotrophin trigger, as a predictor of cycle outcome.
MATERIAL AND METHODS
A prospective intervensional study was conducted at Kamal Al-Samarai Hospital for Infertility Treatment and IVF during the period from December 2020 to September 2021. Ninety infertile women underwent intracytoplasmic sperm injection (ICSI) cycles using antagonist protocol. Moreover, once the patient reached triggering criteria, meticulous recording of follicular index together with serum estrogen level and serum progesterone level are measured. Fresh embryo transfer of cleavage stage embryo is done once serum progesterone level was less than 1.5 ng/mL. A follow-up to confirm pregnancy rate and cycle outcome was done.
RESULTS
The study showed a positive pregnancy rate of 28.9%. The relationship between progesterone follicular index (Prog/FI) ratio and (ICSI) outcome was highly significant with a p value of 0.001. Additionally, an inverse relationship, as the ratio was lower the pregnancy rate was improved, was documented. The receiver operating characteristic (ROC) curve for progesterone follicular index ratio was 0.711 with a cut off value of 0.0354 ng/mL in addition to a sensitivity of 65.6 and a specificity of 65.4.
CONCLUSIONS
The serum progesterone level is an independent factor for the prediction of intracytoplasmic sperm injection (ICSI) outcome, whereas the progesterone follicular index ratio can be used as a potential marker for predicting ICSI outcome in fresh embryo transfer.
PubMed: 37249266
DOI: 10.5603/GP.a2023.0031 -
Pharmacological Research Jul 2023The estrogen receptor-α (ER-α) is a key driver of breast cancer (BC) and the ER-antagonist, tamoxifen, is a central pillar of BC treatment. However, cross-talk between...
The estrogen receptor-α (ER-α) is a key driver of breast cancer (BC) and the ER-antagonist, tamoxifen, is a central pillar of BC treatment. However, cross-talk between ER-α, other hormone and growth factor receptors enables development of de novo resistance to tamoxifen. Herein, we mechanistically dissect the activity of a new class of anti-cancer agents that inhibit multiple growth factor receptors and down-stream signaling for the treatment of ER-positive BC. Using RNA sequencing and comprehensive protein expression analysis, we examined the activity of di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), on the expression and activation of hormone and growth factor receptors, co-factors, and key resistance pathways in ER-α-positive BC. DpC differentially regulated 106 estrogen-response genes, and this was linked to decreased mRNA levels of 4 central hormone receptors involved in BC pathogenesis, namely ER, progesterone receptor (PR), androgen receptor (AR), and prolactin receptor (PRL-R). Mechanistic investigation demonstrated that due to DpC and Dp44mT binding metal ions, these agents caused a pronounced decrease in ER-α, AR, PR, and PRL-R protein expression. DpC and Dp44mT also inhibited activation and down-stream signaling of the epidermal growth factor (EGF) family receptors, and expression of co-factors that promote ER-α transcriptional activity, including SRC3, NF-κB p65, and SP1. In vivo, DpC was highly tolerable and effectively inhibited ER-α-positive BC growth. Through bespoke, non-hormonal, multi-modal mechanisms, Dp44mT and DpC decrease the expression of PR, AR, PRL-R, and tyrosine kinases that act with ER-α to promote BC, constituting an innovative therapeutic approach.
Topics: Humans; Female; Breast Neoplasms; Progesterone; Androgens; Receptors, Prolactin; Prolactin; Tamoxifen; Thiosemicarbazones; ErbB Receptors; Estrogens
PubMed: 37244387
DOI: 10.1016/j.phrs.2023.106806 -
Frontiers in Endocrinology 2022Based on dynamic changes of indicators during controlled ovarian hyperstimulation and of clinical outcomes of suboptimal ovarian response with different protocols, this...
BACKGROUND
Based on dynamic changes of indicators during controlled ovarian hyperstimulation and of clinical outcomes of suboptimal ovarian response with different protocols, this study aimed to summarize the clinical characteristics of SOR and provide clinical recommendations.
METHODS
Data of 125 patients with SOR and 125 controls who had undergone appropriate protocols for fertilization-embryo transfer were collected from a single medical center from January 2017 to January 2019. Basic clinical indexes, including age, BMI, antral-follicle count, infertility time, basic follicle-stimulating hormone, luteinizing hormone, LH/FSH ratio, estradiol, progesterone, testosterone, androstenedione, prolactin, anti-Mullerian hormone, and thyroid stimulating hormone levels, were analyzed using T-test. Dynamic indexes during COH, including amount and days of gonadotropin, sex hormone levels, and number of large/medium/small follicles at specified time periods, were analyzed using T-test and joint diagnosis analysis with ROC curves. Indexes of laboratory and clinical indicators were analyzed using the chi-square test.
RESULTS
For the SOR group, BMI, duration time, and dosage of gonadotropin used for SOR were significantly higher. In the ultra-long/long group, ROC curve analysis showed that the LH/FSH ratio and BMI yielded cutoff values of 0.61 and 21.35 kg/m, respectively. A combined diagnosis of the two indexes showed higher sensitivity (90%) and specificity (59%). In the GnRH-ant group, ROC curve analysis showed an LH level, an LH/FSH ratio on COH day 2, and BMI yielded cutoff values of 2.47 IU/L, 0.57, and 23.95 kg/m, respectively. Combining the two indexes with BMI, both showed increased sensitivity (77%) and specificity (72% and 74%). The estradiol level and progesterone level during the late follicular stage in SOR patients were significantly lower than those in control patients for both protocol groups. At each monitoring time, delayed follicular development was observed. The live-birth rate in fresh cycles of the ultra-long/long group and the live-birth rate in cumulative cycles of the antagonist group in the SOR group were lower than those in the control group.
CONCLUSION
SOR had adverse effects on clinical outcome. We provide some threshold values of basic LH/FSH ratio, BMI, COH day 2 LH, counts of follicles, and levels of estradiol/progesterone to be taken as reference to assist the early recognition of SOR.
Topics: Female; Humans; Progesterone; Retrospective Studies; Follicle Stimulating Hormone; Fertilization in Vitro; Embryo Transfer; Gonadotropins; Estradiol
PubMed: 37228708
DOI: 10.3389/fendo.2022.938926