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Biology of Reproduction Jun 2024Conceptus estrogens and prostaglandins have long been considered the primary signals for maternal recognition of pregnancy (MRP) in the pig. However, loss-of-function...
Conceptus estrogens and prostaglandins have long been considered the primary signals for maternal recognition of pregnancy (MRP) in the pig. However, loss-of-function studies targeting conceptus aromatase genes (CYP19A1 and CYP19A2) and prostaglandin-endoperoxide synthase 2 (PTGS2) indicated that conceptuses can not only signal MRP without estrogens or prostaglandins but can maintain early pregnancy. However, complete loss of estrogen production leads to abortion after day 25 of gestation. Although neither conceptus estrogens nor prostaglandins had a significant effect on early maintenance of CL function alone, the two conceptus factors have a biological relationship. To investigate the role that both conceptus estrogens and prostaglandins have on MRP and maintenance of pregnancy, a triple loss-of function model (TKO) was generated for conceptus CYP19A1, CYP19A2 and PTGS2. In addition, a conceptus CYP19A2-/- model (A2KO) was established to determine the role of placental estrogen during later pregnancy. Estrogen and prostaglandin synthesis were greatly reduced in TKO conceptuses which resulted in a failure to inhibit luteolysis after day 15 of pregnancy despite the presence of conceptuses in the uterine lumen. However, A2KO placentae not only maintained functional CL but were able to maintain pregnancy to day 32 of gestation. Despite the loss of placental CYP19A2 expression, the allantois fluid content of estrogen was not affected as the placenta compensated by expressing CYP19A1 and CYP19A3, which are normally absent in controls. Results suggest conceptuses can signal MRP through production of conceptus PGE or stimulating PGE synthesis from the endometrium through conceptus estrogen. Failure of conceptuses to produce both factors results in failure of MRP and loss of pregnancy.
PubMed: 38904948
DOI: 10.1093/biolre/ioae104 -
Molecular Medicine Reports Aug 2024Estrogens are involved in a number of physiological functions, including in the development of the brain, growth, reproduction and metabolism. The biological actions of... (Review)
Review
Estrogens are involved in a number of physiological functions, including in the development of the brain, growth, reproduction and metabolism. The biological actions of estrogens are achieved by binding to estrogen receptors (ERs) in numerous types of tissues. ERα and ERβ belong to the nuclear receptor superfamily and the G‑protein coupled ER1 (GPER1) is a membrane receptor. The primary biologically active estrogen, 17β‑estradiol demonstrates a high affinity for ERs. Mechanistically, estrogens bind to the ERs in the nucleus, and the complex then dimerize and bind to estrogen response elements (EREs) located in the promoter regions of the target genes. This is referred to as the genomic mechanism of ERs' function. Furthermore, ERs can also act through kinases and other molecular interactions leading to specific gene expression and functions, referred to as the non‑genomic mechanism. While ERα and ERβ exert their functions via both genomic and non‑genomic pathways, GPER1 exerts its function primarily via the non‑genomic pathways. Any aberrations in ER signaling can lead to one of a number of diseases such as disorders of growth and puberty, fertility and reproduction abnormalities, cancer, metabolic diseases or osteoporosis. In the present review, a focus is placed on three target tissues of estrogens, namely the bones, the breasts and the brain, as paradigms of the multiple facets of the ERs. The increasing prevalence of breast cancer, particularly hormone receptor‑positive breast cancer, is a challenge for the development of novel antihormonal therapies other than tamoxifen and aromatase inhibitors, to minimize toxicity from the long treatment regimens in patients with breast cancer. A complete understanding of the mechanism of action of ERs in bones may highlight options for novel targeted treatments for osteoporosis. Likewise, the aging of the brain and related diseases, such as dementia and depression, are associated with a lack of estrogen, particularly in women following menopause. Furthermore, gender dysphoria, a discordance between experienced gender and biological sex, is commonly hypothesized to emerge due to discrepancies in cerebral and genital sexual differentiation. The exact role of ERs in gender dysphoria requires further research.
Topics: Humans; Receptors, Estrogen; Signal Transduction; Brain; Bone and Bones; Breast; Animals; Female; Estrogens; Receptors, G-Protein-Coupled
PubMed: 38904201
DOI: 10.3892/mmr.2024.13268 -
Directive clinique n 451 : Épaississement asymptomatique de l'endomètre chez les femmes ménopausées.Journal of Obstetrics and Gynaecology... Jun 2024Formuler des stratégies d'évaluation clinique de l'épaississement de l'endomètre confirmé à l'échographie chez les femmes ménopausées n'ayant pas de saignement.
OBJECTIF
Formuler des stratégies d'évaluation clinique de l'épaississement de l'endomètre confirmé à l'échographie chez les femmes ménopausées n'ayant pas de saignement.
POPULATION CIBLE
Femmes ménopausées de tous âges. RéSULTATS: Réduire les interventions et examens invasifs inutiles chez les femmes présentant un épaississement asymptomatique de l'endomètre tout en évaluant de manière sélective les cas impliquant un risque de cancer de l'endomètre. BéNéFICES, RISQUES ET COûTS: L'adoption de ces recommandations devrait éviter angoisses, douleurs et risques de complications opératoires inutiles aux femmes ménopausées. Ces mesures devraient aussi réduire les coûts pour le système de santé en éliminant les interventions inutiles. DONNéES PROBANTES: Des recherches ont été faites dans les bases de données Medline, Cochrane et PubMed pour répertorier les articles pertinents évalués par des pairs et publiés en anglais dans la période de 1995 à 2022 qui traitent notamment des sujets suivants : épaississement asymptomatique de l'endomètre, cancer de l'endomètre, saignements postménopausiques, échographie endovaginale, biopsie de l'endomètre, sténose cervicale, hormonothérapies et endomètre, tamoxifène, tibolone et inhibiteurs de l'aromatase. Seuls les résultats de revues systématiques avec méta-analyse, d'essais cliniques randomisés, d'essais cliniques comparatifs et d'études observationnelles ont été retenus. MéTHODES DE VALIDATION: Les auteurs ont évalué la qualité des données probantes et le niveau des recommandations en utilisant l'échelle GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Voir l'annexe A (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et faibles). PROFESSIONNELS CONCERNéS: Médecins, incluant les gynécologues, obstétriciens, médecins de famille, radiologistes, anatomopathologistes et internistes; infirmières et infirmières praticiennes; stagiaires en médecine, y compris étudiants en médecine, résidents et moniteurs cliniques; et autres prestataires de soins auprès de la population ménopausée. RéSUMé DES MéDIAS SOCIAUX: Les femmes ménopausées présentent souvent un épaississement de la muqueuse utérine à l'échographie. En l'absence de saignements, un endomètre de moins de 11 mm d'épaisseur est rarement un problème grave, mais doit être évalué par un professionnel de la santé.
PubMed: 38901795
DOI: 10.1016/j.jogc.2024.102590 -
Journal of Obstetrics and Gynaecology... Jun 2024To formulate strategies for clinical assessments for endometrial thickening on ultrasound in a postmenopausal woman without bleeding.
OBJECTIVE
To formulate strategies for clinical assessments for endometrial thickening on ultrasound in a postmenopausal woman without bleeding.
TARGET POPULATION
Postmenopausal women of any age.
OUTCOMES
To reduce unnecessary invasive interventions and investigations in women with asymptomatic endometrial thickening while selectively investigating women at risk for endometrial cancer.
BENEFITS, HARMS, AND COSTS
It is anticipated that the adoption of these recommendations would save postmenopausal women unnecessary anxiety, pain, and risk of procedural complications. It is also expected to decrease the cost to the health care system by eliminating unnecessary interventions.
EVIDENCE
English language articles from Medline, Cochrane, and PubMed databases for relevant peer-reviewed articles dating from 1995 to 2022 (e.g., asymptomatic endometrial thickness, endometrial cancer, postmenopausal bleeding, transvaginal ultrasound, endometrial biopsy, cervical stenosis, hormone therapies and the endometrium, tamoxifen, tibolone, aromatase inhibitors). Results were restricted to systematic reviews and meta-analyses, randomized controlled trials/controlled clinical trials, and observational studies.
VALIDATION METHODS
The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations).
INTENDED AUDIENCE
Physicians, including gynaecologists, obstetricians, family physicians, radiologists, pathologists, and internists; nurse practitioners and nurses; medical trainees, including medical students, residents, and fellows; and other providers of health care of the postmenopausal population.
SOCIAL MEDIA ABSTRACT
Postmenopausal women often have a thickening of the lining of the uterus found during ultrasound. Without bleeding, an endometrium <11 mm is rarely a serious problem but should be evaluated by a health care provider.
PubMed: 38901794
DOI: 10.1016/j.jogc.2024.102591 -
European Journal of Obstetrics,... Jun 2024To evaluate the efficacy of two different regimens of Letrozole, an aromatase inhibitor, in the management of ectopic pregnancy compared to methotrexate.
OBJECTIVE
To evaluate the efficacy of two different regimens of Letrozole, an aromatase inhibitor, in the management of ectopic pregnancy compared to methotrexate.
STUDY DESIGN
This randomized controlled trial was conducted on 88 women diagnosed with ectopic pregnancy with a baseline level of serum beta-human chorionic gonadotropin under 3000 mIU/mL between June 30, 2023, and December 30, 2023, at the Department of Obstetrics and Gynecology of the Vali-e-Asr Hospital affiliated with Tehran University of Medical Sciences. Participants were allocated into either methotrexate (n = 43), 5-day course Letrozole (n = 24), or 10-day course Letrozole (n = 21) treatments. The methotrexate group received a single dose of 50 mg/m dosage intramuscular methotrexate. The 5-day Letrozole group received a 2.5 mg Letrozole tablet three times daily for 5 days, whereas the 10-day Letrozole group received a 2.5 mg Letrozole tablet twice daily for 10 days. The primary outcome was the treatment response, defined as the achievement of a negative serum beta-human chorionic level without the need for additional methotrexate treatment or surgery. The secondary outcomes were the need for additional methotrexate dose or laparoscopic surgery intervention. The trial protocol was prospectively registered in ClinicalTrials.gov with code NCT05918718.
RESULTS
The treatment response rates in methotrexate, 5-day Letrozole, and 10-day Letrozole groups were 76.7 %, 75.0 %, and 90.5 %, respectively, with no significant differences between the groups (P-value = 0.358). A total of 10 (23.3 %) patients from the methotrexate group, 3 (12.5 %) from the 5-day Letrozole group, and 2 (9.5 %) from the 10-day Letrozole group required an additional methotrexate dose, with no significant differences between the groups (P-value = 0.307). Furthermore, only 3 (12.5 %) patients, all from the 5-day Letrozole group, were suspected of tubal rupture and underwent surgery (P-value = 0.016).
CONCLUSION
Our findings suggest Letrozole as a safe alternative to methotrexate in treating stable ectopic pregnancies, with a favorable treatment response rate. However, there is still a need for future larger studies to determine the applicability of Letrozole in the EP management. Also, the non-significant higher effectiveness of the 10-day Letrozole regimen than the 5-day Letrozole group underscores the need for future research to determine the optimal Letrozole regimen for the management of ectopic pregnancy.
PubMed: 38901084
DOI: 10.1016/j.ejogrb.2024.06.026 -
Reproductive Medicine and Biology 2024To verify the effectiveness of embryo transfer (ET) using cryopreserved embryo as fertility preservation (FP).
PURPOSE
To verify the effectiveness of embryo transfer (ET) using cryopreserved embryo as fertility preservation (FP).
METHODS
This study was a questionnaire survey. The total number of embryo cryopreservation (EC) was investigated between 2014 and 2020. And for patients who underwent ET among study period, details of EC, outcome of ET, number of live births, and mortality were investigated.
RESULTS
Of the 150 facilities, 114 responded (76.0%). A total of 1420 EC were performed during the study period; and ET was performed for 417 patients. Breast cancer was the most common primary disease. A total of 199 live births (including prospective) were obtained by ET; 1.7 EC and 2.2 ET were performed per patient, and live birth rate was 21.4% per ET (28.1% on 35-37-year-old patients). The number of EC and ET increased with age. The final birth rate, including pregnancies other than FP, was 51.8%. Ovarian stimulation with aromatase inhibitors was commonly used, although with no effect on live birth rates. Random start stimulation was also common, experienced by 36.3% of breast cancer patients.
CONCLUSION
Reproductive outcomes of ETs following EC as FP are acceptable. This research project was registered in the University Hospital Medical Information Network (UMIN000043664).
PubMed: 38899000
DOI: 10.1002/rmb2.12581 -
Cancer Medicine Jun 2024The optimal adjuvant endocrine therapy (ET) in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 positive (HER2+) premenopausal breast cancer...
BACKGROUND
The optimal adjuvant endocrine therapy (ET) in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 positive (HER2+) premenopausal breast cancer (BC) remains unclear. Moreover, the benefit and clinical indications of ovarian suppression (OS) is poorly elucidated. We described real-world patterns surrounding choice of ET and clinicopathologic features which predicted treatment with OS in a contemporary cohort of premenopausal women with HR+/HER2+ BC.
METHODS
This retrospective analysis included premenopausal patients with nonmetastatic HR+/HER2+ BC from the CancerLinQ Discovery database from January 2010 to May 2020. Women were less than 50 years and received chemotherapy, anti-HER2 therapy, and ET. They were categorized into 1 of 4 groups based on type of ET prescribed at initiation: aromatase inhibitor (AI) + OS, OS, tamoxifen + OS, or tamoxifen. Multivariable logistic regression assessed associations between clinicopathologic features and OS use.
RESULTS
Out of 360,540 patients with BC, 937 were included. The majority (n = 818, 87%) were prescribed tamoxifen, whereas 4 (0.4%), 50 (5.3%), and 65 (6.9%) received OS, tamoxifen + OS and AI + OS, respectively. No clinicopathologic features predicted OS use apart from age; patients <35 years were more likely to receive OS compared with those ≥35 years (odds ratio 2.33, p < 0.001).
CONCLUSIONS
This is the first real-world study evaluating ET treatment patterns in HR+/HER2+ premenopausal BC. OS use was uncommon and the majority received tamoxifen as the preferred ET regardless of most clinicopathologic risk factors. Additional research is needed to optimize ET decisions in young women with this distinct BC subtype.
Topics: Humans; Female; Breast Neoplasms; Premenopause; Adult; Retrospective Studies; Receptor, ErbB-2; Chemotherapy, Adjuvant; Antineoplastic Agents, Hormonal; Tamoxifen; Aromatase Inhibitors; Middle Aged; Receptors, Estrogen; Receptors, Progesterone; Ovary
PubMed: 38895891
DOI: 10.1002/cam4.7317 -
Journal of Biomolecular Structure &... Jun 2024Estrogen receptor-positive breast cancer represents itself as the most prevalent malignancy among postmenopausal women. One of the promising therapeutic approaches...
Estrogen receptor-positive breast cancer represents itself as the most prevalent malignancy among postmenopausal women. One of the promising therapeutic approaches involves the use of Aromatase inhibitors, which competitively bind to Aromatase, reducing estrone and estradiol levels. While current drugs have improved survival rates, they are not without adverse effects. Consequently, this study explores the computational screening of medicinally relevant compounds derived from okra () for potential Aromatase inhibition. Molecular docking employing AMDock v1.5.2 was utilized to assess binding affinities with Aromatase (PDB:3EQM). Subsequently, in-depth molecular interactions were examined using Discovery Studio Visualizer v4.5, and the stability of docked complexes was evaluated molecular dynamics with the GROMACS package, focusing on RMSD, RMSF, H-bond count, SASA, Free energy landscape, Principal Component Analysis and binding affinity assessment. The pharmacokinetic properties of the okra compounds were predicted using admetSAR v2.0. Our findings highlight Quercetin 3-gentiobioside as a standout candidate, demonstrating superior binding affinity (-10 kcal/mol) and an estimated Ki of 46.77 nM compared to letrozole and other okra compounds. Molecular dynamic analysis confirms the stability of Quercetin 3-gentiobioside binding in terms of H-bonds and conformational integrity. In conclusion, our computational investigation identifies Quercetin 3-gentiobioside, along with Quercetin 3-O-rutinoside and Hyperin, as promising candidates for preclinical studies in the pursuit of potential Aromatase inhibitors.Communicated by Ramaswamy H. Sarma.
PubMed: 38887049
DOI: 10.1080/07391102.2024.2335301 -
Translational Cancer Research May 2024Chidamide (CHI) is a subtype-selective histone deacetylase inhibitor (HDACI) developed in China and approved as a second-line treatment combined with the aromatase...
BACKGROUND
Chidamide (CHI) is a subtype-selective histone deacetylase inhibitor (HDACI) developed in China and approved as a second-line treatment combined with the aromatase inhibitor for hormone receptor-positive (HR)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer. However, drug resistance is commonly occurred after a long period of medication. This study aimed to investigate the characterization of induced resistance to CHI and explore the potential cross-resistance to chemotherapeutic agents.
METHODS
CHI with gradually increasing concentrations was added to breast cancer MCF7 cells to establish a CHI-resistant MCF7 (MCF7-CHI-R) cell line. Cell counting kit-8 (CCK-8) assays were performed to detect half-maximal inhibitory concentration (IC) of CHI. Colony formation was used to determine the proliferation inhibition rate. Western blot analysis was conducted to detect expressions of protein related with cell cycle, apoptosis, ferroptosis, and histone deacetylase (HDAC). Flow cytometry was used to analyze apoptosis and cell cycle.
RESULTS
The IC value of CHI of MCF7-CHI-R cells was increased in comparison with MCF7 cells. And CHI led to cell cycle arrest and ferroptosis, which were not exhibited in MCF7-CHI-R cells. Moreover, HDAC activity decreased in MCF7-CHI-R cells in comparison with MCF7 cells, and HDAC1 and HDAC10 might be involved in the resistance to CHI. In addition, MCF7-CHI-R cells were resistant to gemcitabine (GEM), doxorubicin (ADM), docetaxel (DXT), albumin-bound paclitaxel (nab-PTX) and paclitaxel (PTX).
CONCLUSIONS
The MCF7-CHI-R was established and the anti-ferroptosis pathway activation was involved in the resistance of MCF-CHI-R cells. Also, MCF7-CHI-R cells were resistant to GEM, ADM, DXT, nab-PTX and PTX.
PubMed: 38881946
DOI: 10.21037/tcr-23-2169 -
Gynecologic Oncology Reports Aug 2024• gene amplification occurs in 7% of uterine carcinosarcoma.•The presence of gene amplification in recurrent uterine carcinosarcoma may be targeted by aromatase...
• gene amplification occurs in 7% of uterine carcinosarcoma.•The presence of gene amplification in recurrent uterine carcinosarcoma may be targeted by aromatase inhibitors.• gene amplification may be identified through immunohistochemical staining for estrogen receptor followed by fluorescence in situ hybridization or tumor targeted gene sequencing.
PubMed: 38881561
DOI: 10.1016/j.gore.2024.101426