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World Journal of Surgical Oncology Jun 2024This study aimed to evaluate the oncological and reproductive outcomes of fertility-preserving re-treatment in progestin-resistant endometrial carcinoma (EC) and...
OBJECTIVE
This study aimed to evaluate the oncological and reproductive outcomes of fertility-preserving re-treatment in progestin-resistant endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) women who desire to maintain their fertility.
METHODS
Our study included 61 progestin-resistant EC/AEH patients. These patients underwent treatment with gonadotropin-releasing hormone agonist (GnRHa) solely or a combination of GnRHa with levonorgestrel-releasing intrauterine system (LNG-IUD) or aromatase inhibitor (AI). Histological evaluations were performed every 3-4 months. Upon achieving complete remission (CR), we recommended maintenance treatments including LNG-IUD, cyclical oral contraceptives, or low-dose cyclic progestin until they began attempting conception. Regular follow-up was conducted for all patients. The chi-square method was utilized to compare oncological and fertility outcomes, while the Cox proportional hazards regression analysis helped identify risk factors for CR, recurrence, and pregnancy.
RESULTS
Overall, 55 (90.2%) patients achieved CR, including 90.9% of AEH patients and 89.7% of EC patients. The median re-treatment time was 6 months (ranging from 3 to 12 months). The CR rate for GnRHa alone, GnRHa + LNG-IUD and GnRHa + AI were 80.0%, 91.7% and 93.3%, respectively. After a median follow-up period of 36 months (ranging from 3 to 96 months), 19 women (34.5%) experienced recurrence, 40.0% in AEH and 31.4% in EC patients, with the median recurrence time of 23 months (ranging from 6 to 77 months). Among the patients who achieved CR, 39 expressed a desire to conceive, 20 (51.3%) became pregnant, 11 (28.2%) had successfully deliveries, 1 (5.1%) was still pregnant, while 8 (20.5%) suffered miscarriages.
CONCLUSION
GnRHa-based fertility-sparing treatment exhibited promising oncological and reproductive outcomes for progestin-resistant patients. Future larger multi-institutional studies are necessary to confirm these findings.
Topics: Humans; Female; Endometrial Neoplasms; Adult; Retrospective Studies; Fertility Preservation; Endometrial Hyperplasia; Progestins; Follow-Up Studies; Pregnancy; Drug Resistance, Neoplasm; Gonadotropin-Releasing Hormone; Levonorgestrel; Middle Aged; Prognosis; Intrauterine Devices, Medicated; Neoplasm Recurrence, Local; Pregnancy Rate; Aromatase Inhibitors; Antineoplastic Agents, Hormonal
PubMed: 38918837
DOI: 10.1186/s12957-024-03439-w -
European Journal of Endocrinology Jun 2024Neuroendocrine tumors (NET) are malignant neoplasms that can be associated with specific hormonal syndromes. We describe a novel syndrome of postmenopausal vaginal...
Neuroendocrine tumors (NET) are malignant neoplasms that can be associated with specific hormonal syndromes. We describe a novel syndrome of postmenopausal vaginal bleeding and ovarian estradiol overproduction due to ovarian NET localizations. An extensive workup was performed for two index patients with ovarian metastases of small bowel neuroendocrine tumors and symptoms of postmenopausal vaginal bleeding. Clinically significant ovarian estrogen production was demonstrated by a combination of ovarian vein sampling and normalization of circulating estrogen levels after oophorectomy. Immunohistochemical analyses revealed marked aromatase immunoactivity in the ovarian NET cells, while CYP17A1 and SF-1 were detected in the adjacent ovarian stromal cells but not the NET cells. Ex vivo and in vivo endocrine tests were unable to identify a paracrine mechanism of ovarian estradiol overproduction by NET cells. A retrospective search of electronic medical records revealed that 21% (14/66) of postmenopausal patients with an ovarian NET localization reported symptoms of vaginal blood loss. Together, these findings support the presence of a novel NET-associated hormonal syndrome.
PubMed: 38917055
DOI: 10.1093/ejendo/lvae075 -
Scientific Reports Jun 2024Hydrogen peroxide is considered deleterious molecule that cause cellular damage integrity and function. Its key redox signaling molecule in oxidative stress and exerts...
Hydrogen peroxide is considered deleterious molecule that cause cellular damage integrity and function. Its key redox signaling molecule in oxidative stress and exerts toxicity on a wide range of organisms. Thus, to understand whether oxidative stress alters visual development, zebrafish embryos were exposed to HO at concentration of 0.02 to 62.5 mM for 7 days. Eye to body length ratio (EBR) and apoptosis in retina at 48 hpf, and optomotor response (OMR) at 7 dpf were all measured. To investigate whether hydrogen peroxide-induced effects were mediated by oxidative stress, embryos were co-incubated with the antioxidant, glutathione (GSH) at 50 μM. Results revealed that concentrations of HO at or above 0.1 mM induced developmental toxicity, leading to increased mortality and hatching delay. Furthermore, exposure to 0.1 mM HO decreased EBR at 48 hpf and impaired OMR visual behavior at 7 dpf. Additionally, exposure increased the area of apoptotic cells in the retina at 48 hpf. The addition of GSH reversed the effects of HO, suggesting the involvement of oxidative stress. HO decreased the expression of eye development-related genes, pax6α and pax6β. The expression of apoptosis-related genes, tp53, casp3 and bax, significantly increased, while bcl2α expression decreased. Antioxidant-related genes sod1, cat and gpx1a showed decreased expression. Expression levels of estrogen receptors (ERs) (esr1, esr2α, and esr2β) and ovarian and brain aromatase genes (cyp19a1a and cyp19a1b, respectively) were also significantly reduced. Interestingly, co-incubation of GSH effectivity reversed the impact of HO on most parameters. Overall, these results demonstrate that HO induces adverse effects on visual development via oxidative stress, which leads to alter apoptosis, diminished antioxidant defenses and reduced estrogen production.
Topics: Animals; Oxidative Stress; Apoptosis; Zebrafish; Hydrogen Peroxide; Antioxidants; Zebrafish Proteins; Glutathione; Retina; Estrogens; Gene Expression Regulation, Developmental; Embryo, Nonmammalian; Vision, Ocular
PubMed: 38914633
DOI: 10.1038/s41598-024-64933-5 -
Chemosphere Jun 2024The water accommodated fraction (WAF) of spilled crude oil is a severe threat to the health of marine fish. This study was conducted to investigate the effects of...
The water accommodated fraction (WAF) of spilled crude oil is a severe threat to the health of marine fish. This study was conducted to investigate the effects of short-term embryonic exposure to the WAF on the ovarian development and reproductive capability of F0 adult female marine medaka (Oryzias melastigma). Following embryonic exposure to the WAF with nominal total petroleum hydrocarbon concentrations of 0.5, 5, 50, and 500 μg/L for 7 days, the number of spawned eggs and gonadosomatic indices of F0 adult females were significantly reduced at 130 days postfertilization. In these F0 adult females, the proportion of mature oocytes was significantly lower, the level of 17β-estradiol was lower, and the level of testosterone was greater than those in control group. The mRNA levels of the follicle-stimulating hormone β subunit, luteinizing hormone β subunit, cytochrome P450 aromatase 19b, estrogen receptor α and β, and androgen receptor α and β genes were upregulated, while the mRNA level of the salmon-type gonadotropin-releasing hormone was downregulated in F0 adult females exposed to the WAF during the embryonic stage. Additionally, the methylation level of vitellogenin (vtg) in F0 adult females was significantly elevated, this might have, in turn, downregulated the mRNA level of vtg. The mortality rate of the unexposed F1 embryos was significantly increased and the hatching success was significantly reduced. These results collectively indicated the necessity of incorporating and evaluating the effects of short-term early-life exposure to crude oil in the assessment of risks to the reproductive health of marine fish.
PubMed: 38906194
DOI: 10.1016/j.chemosphere.2024.142616 -
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