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1.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070207

RESUMO

In domestic ruminants, endometrial receptivity is related to successful pregnancy and economic efficiency. Despite several molecules having been reported in the past regarding endometrial receptivity regulation, much regarding the mechanism of endometrial receptivity regulation remains unknown due to the complex nature of the trait. In this work, we demonstrated that the cysteine-rich transmembrane bone morphogenetic protein (BMP) regulator 1 (CRIM1) served as a novel regulator in the regulation of goat endometrial receptivity in vitro. Our results showed that hormones and IFN-τ increased the expression of CRIM1 in goat endometrial epithelial cells (EECs). Knockdown of CRIM1 via specific shRNA hindered cell proliferation, cell adhesion and prostaglandins (PGs) secretion and thus derailed normal endometrial receptivity. We further confirmed that receptivity defect phenotypes due to CRIM1 interference were restored by ATG7 overexpression in EECs while a loss of ATG7 further impaired receptivity phenotypes. Moreover, our results showed that changing the expression of ATG7 affected the reactive oxygen species (ROS) production. Moreover, mR-143-5p was shown to be a potential upstream factor of CRIM1-regulated endometrial receptivity in EECs. Overall, these results suggest that CRIM1, as the downstream target of miR-143-5p, has effects on ATG7-dependent autophagy, regulating cell proliferation, cell adhesion and PG secretion, and provides a new target for the diagnosis and treatment of early pregnancy failure and for improving the success rates of artificial reproduction.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas/fisiologia , Implantação do Embrião/genética , Endométrio/fisiologia , Cabras/fisiologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Autofagia/fisiologia , Proteína 7 Relacionada à Autofagia/deficiência , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/fisiologia , Receptores de Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Receptores de Proteínas Morfogenéticas Ósseas/genética , Adesão Celular , Proliferação de Células , Células Cultivadas , Implantação do Embrião/fisiologia , Endométrio/citologia , Endométrio/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Estradiol/farmacologia , Feminino , Técnicas de Silenciamento de Genes , Cabras/genética , Interferon Tipo I/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Biológicos , Gravidez , Proteínas da Gravidez/farmacologia , Progesterona/farmacologia , Prostaglandinas/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima
2.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33808965

RESUMO

Polycystic ovary syndrome (PCOS) is a major anovulatory infertility affecting a great proportion of women of childbearing age and is associated with obesity, insulin resistance and chronic inflammation. Poor endometrial receptivity and recurrent implantation failure are major hurdles to the establishment of pregnancy in women with PCOS. The accumulating body of evidence obtained from experimental and clinical studies suggests a link between inherent adaptive and innate immune irregularities and aberrant endometrial features in PCOS. The use of conventional therapeutic interventions such as lifestyle modification, metformin and ovarian stimulation has achieved limited clinical success in restoring ovulation and endometrial receptivity in women with PCOS. Unlike other immunosuppressive drugs prescribed in the clinical management of autoimmune and inflammatory disorders that may have deleterious effects on fertility and fetal development, preclinical studies in mice and in women without PCOS but with repeated implantation failure revealed potential therapeutic benefits for the use of low-dose tacrolimus in treating female infertility. Improved systemic and ovarian immune functions, endometrial progesterone receptor and coreceptor expressions and uterine vascular adaptation to pregnancy were among features of enhanced progesterone-receptor sensitivity in the low-dose tacrolimus-treated mouse model of the disease. In this review, we have compiled available experimental and clinical data in literature on endometrial progesterone resistance and current therapeutic options, as well as mechanisms of actions and reported outcomes relevant to the potential therapeutic benefits for the use of low-dose tacrolimus in treating PCOS-associated female infertility.


Assuntos
Endométrio/efeitos dos fármacos , Infertilidade Feminina/tratamento farmacológico , Síndrome do Ovário Policístico/tratamento farmacológico , Tacrolimo/uso terapêutico , Relação Dose-Resposta a Droga , Endométrio/anormalidades , Endométrio/patologia , Feminino , Humanos , Infertilidade Feminina/genética , Infertilidade Feminina/patologia , Resistência à Insulina/genética , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/patologia , Gravidez , Doenças Uterinas/genética
3.
Res Vet Sci ; 136: 220-226, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33689878

RESUMO

Endometritis is a major disease in productive bovines, and is also caused by conditional pathogens after delivery. The integrity and activity of bovine endometrial epithelial cells (bEECs) determine the development of endometritis. Tanshinone IIA, a compound purified from Salvia miltiorrhiza bunge, has been reported to have anti-inflammatory effects. The aim of this study was to investigate the anti-inflammatory effects of tanshinone IIA in the LPS-induced inflammatory response of bEECs. The results showed that tanshinone IIA inhibited the mRNA expression levels of COX-2 and iNOS, and reduced the expression levels of IL-1ß, TNF-α, IL-6 and IL-8 induced by LPS. In addition, we found that tanshinone IIA inhibited the level of MDA, but increased the activities of CAT and SOD. To evaluate the anti-inflammatory mechanism of tanshinone IIA, we examined the activation of Nrf2. The results showed that the Nrf2 signaling pathway was significantly activated by tanshinone IIA. In conclusion, these results showed that tanshinone IIA exhibited anti-inflammatory and antioxidative effects by activating the Nrf2 signaling pathway.


Assuntos
Abietanos/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Bovinos/fisiologia , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Endométrio/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Feminino , Lipopolissacarídeos/efeitos adversos
4.
Eur J Pharmacol ; 896: 173924, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33548216

RESUMO

The objectives of this study were to investigate the effects of KISS1 94-121 fragment on the contractility of non-pregnant and pregnant rat uteri, and to determine the uterine and myometrial expressions of Kiss1r. Uterine muscle strips were obtained from non-pregnant Sprague-Dawley rats in oestrous phase and from pregnant rats on gestational days 5, 15, 18, 20 or 22. The in vitro contractility measurements were carried out in an isolated organ bath in the presence of KISS1 94-121. Experiments with 5-day pregnant tissues were also performed in the presence of kisspeptin-234 trifluoroacetate. The mRNA and protein expressions of Kiss1r were measured by RT-PCR and Western blot analysis, while localizations of receptors were defined by fluorescent immunohistochemistry. KISS1 94-121 induced a dose-dependent relaxation both in non-pregnant and pregnant intact and endometrium-denuded uteri. A gradual decrease was found in the uterine expressions of Kiss1r mRNA and protein towards the end of the gestational period, and it was further confirmed by the immunohistochemical results. The significant majority of Kiss1r is found in the myometrium, however the few endometrial Kiss1r also influences the uterine contractions. The relaxing effect of kisspeptin is continuously reduced towards the end of gestational period in parallel with the reduction of Kiss1r expression. Our results suggest a putative role of kisspeptin in the maintenance of uterine quiescence that may have significance in miscarriage or preterm contractions.


Assuntos
Kisspeptinas/farmacologia , Miométrio/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores de Kisspeptina-1/agonistas , Contração Uterina/efeitos dos fármacos , Animais , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Feminino , Técnicas In Vitro , Miométrio/metabolismo , Gravidez , Ratos Sprague-Dawley , Receptores de Kisspeptina-1/genética , Receptores de Kisspeptina-1/metabolismo , Transdução de Sinais
5.
Ecotoxicol Environ Saf ; 208: 111606, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396126

RESUMO

Mancozeb is a metal-containing ethylene bis-dithiocarbamate fungicide widely used in agriculture. Ethylene thiourea (ETU) is the primary metabolite of Mancozeb. Mancozeb has been associated with spontaneous abortions and abnormal menstruation in women. However, the effects of Mancozeb and ETU on embryo attachment remain unknown. The human blastocyst surrogate trophoblastic spheroids (JEG-3), endometrial epithelial surrogate adenocarcinoma cells (Ishikawa), or human primary endometrial epithelial cells (EECs) monolayer were used in the spheroid attachment models. Ishikawa and EECs were pretreated with different concentrations of Mancozeb or ETU for 48 h before the attachment assay. Gene expression profiles of Ishikawa cells were examined to understand how Mancozeb modulates endometrial receptivity with Microarray. The genes altered by Mancozeb were confirmed by qPCR and compared with the ETU treated groups. Mancozeb and ETU treatment inhibited cell viability at 10 µg/mL and 5000 µg/mL, respectively. At non-cytotoxic concentrations, Mancozeb at 3 µg/mL and ETU at 300 µg/mL reduced JEG-3 spheroid attachment onto Ishikawa cells. A similar result was observed with human primary endometrial epithelial cells. Mancozeb at 3 µg/mL modified the transcription of 158 genes by at least 1.5-fold in Microarray analysis. The expression of 10 differentially expressed genes were confirmed by qPCR. Furthermore, Mancozeb decreased spheroid attachment possibly through downregulating the expression of endometrial estrogen receptor ß and integrin ß3, but not mucin 1. These results were confirmed in both overexpression and knockdown experiments and co-culture assay. Mancozeb but not its metabolite ETU reduced spheroid attachment through modulating gene expression profile and decreasing estrogen receptor ß and integrin ß3 expression of endometrial epithelial cells.


Assuntos
Adesão Celular/efeitos dos fármacos , Endométrio/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Receptor beta de Estrogênio/metabolismo , Fungicidas Industriais/toxicidade , Integrina beta3/metabolismo , Maneb/toxicidade , Esferoides Celulares/efeitos dos fármacos , Zineb/toxicidade , Blastocisto/citologia , Blastocisto/efeitos dos fármacos , Blastocisto/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Regulação para Baixo , Endométrio/citologia , Endométrio/metabolismo , Células Epiteliais/metabolismo , Receptor beta de Estrogênio/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Integrina beta3/genética , Gravidez , Esferoides Celulares/metabolismo
6.
Ecotoxicol Environ Saf ; 207: 111511, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33254391

RESUMO

Decidualization, which endows the endometrium competency to adopt developing embryo and maintain appropriate milieu for following growth, is a pivotal process for human pregnancy. The delicate collaboration between ovarian steroid hormones estrogen and progesterone governs the process of decidualization and subsequent establishment of embryo implantation. Mycotoxin zearalenone (ZEA) is well known as endocrine disruptor due to its potent estrogenic activity. In this study, we investigated effects of ZEA on decidualization of human endometrial stromal cells. Results indicated that ZEA exhibited its inhibitory action through nuclear translocation of ERα. ZEA exposure led to dampened progress of decidualization, which could be attenuated by estrogen receptor antagonist. Notably, resveratrol (RSV) administration restored impaired decidualization process by induction of anti-oxidative gene glutathione peroxidase 3 (GPX3). This study provides novel insights into the mechanism underlying adverse effects of ZEA in human decidual stromal cells and suggests RSV a potential therapeutic candidate to alleviate ZEA-induced cytotoxicity during decidualization.


Assuntos
Disruptores Endócrinos/toxicidade , Estrogênios não Esteroides/toxicidade , Substâncias Protetoras/farmacologia , Resveratrol/farmacologia , Zearalenona/toxicidade , Células Cultivadas , Decídua/efeitos dos fármacos , Implantação do Embrião/efeitos dos fármacos , Endométrio/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Receptor alfa de Estrogênio , Estrogênios/farmacologia , Feminino , Humanos , Gravidez , Progesterona/farmacologia , Células Estromais/efeitos dos fármacos
7.
Microvasc Res ; 133: 104074, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32949576

RESUMO

Angiogenesis, where vascular endothelial growth factor (VEGF) is critically involved, is an important factor in endometrial receptivity. Angio-miRNAs form a special class of microRNAs (miRNAs) that target angiogenic genes and regulate angiogenesis. Various studies have shown that ovarian stimulation and exogenous progesterone affect endometrial vascular density. The present research aimed to assess the impact of HMG/HCG and progesterone on miR-16-5p, VEGF protein expression, and angiogenesis in the mouse endometrium during the preimplantation period. Forty adult female mice were divided into four groups: 1) control, 2) ovarian stimulation (HMG and 48 h after HCG IP), 3) progesterone (progesterone IP for 3 days), 4) ovarian stimulation + progesterone (HMG and 48 h after HCG IP) + (progesterone IP for 3 days) groups.The mice were sacrificed 96 h following HCG administration. miR-16-5p, VEGF protein expression, and CD31-positive cell (Endothelial cell) density were specified.The results showed that endothelial cell density,VEGF protein, and miR-16-5p expression increased in all treatment groups, with the maximum increase belonging to the ovarian stimulation + progesterone group. This study provides evidence that ovarian stimulation and progesterone administration enhance endometrial angiogenesis through VEGF protein upregulation. Furthermore, except for miR-16-5p, other miRNAs and molecules appear to be involved in angiogenic pathways, thereby requiring further studies.


Assuntos
Gonadotropina Coriônica/farmacologia , Endométrio/irrigação sanguínea , Endométrio/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Fármacos para a Fertilidade Feminina/farmacologia , Menotropinas/farmacologia , MicroRNAs/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Indução da Ovulação , Progesterona/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Endométrio/metabolismo , Células Endoteliais/metabolismo , Feminino , Camundongos , MicroRNAs/genética , Transdução de Sinais
8.
J Ethnopharmacol ; 265: 113288, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32841695

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Tokishakuyakusan (TSS) is a Kampo medicine that is prescribed for the treatment of infertility in Japan. However, its precise mechanism of action remains unclear. AIM OF THE STUDY: Leukemia inhibitory factor (LIF) in the endometrium plays an indispensable role in embryo implantation and is linked to infertility or implantation failure. Previously, we demonstrated that TSS ameliorated implantation failure induced by mifepristone (RU-486), an antagonist of progesterone, in rats. Herein, we aimed to clarify whether the ameliorating effect of TSS on implantation failure in the rat model involves endometrial LIF. Additionally, we determined whether decidualization, the dysfunction of which is linked to infertility or implantation failure similar to LIF, progesterone, and other implantation-related factors, are involved in the effect of TSS. MATERIALS AND METHODS: The implantation failure rat model was developed via the subcutaneous administration of RU-486 (7 mg/kg) on day 3 post-coitus. Sesame oil was administered as the vehicle control. Rats were fed a diet containing 1% or 3% TSS or a control diet from day 13 pre-coitus. Subsequently, the implantation sites were assessed, and plasma progesterone levels were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) on day 8 post-coitus. The LIF mRNA of the endometrial gland, which was segmented via laser-microdissection from the endometrial tissue, was measured, and endometrial LIF immunostaining was carried out on day 5. The gene expression of different factors related to implantation, including decidualization and progesterone-responsiveness on days 5 and 6, were measured. The human endometrial Ishikawa cell line derived from human adenocarcinoma was treated with TSS (30-300 µg/mL) for 24 h, and the LIF concentrations in the cell culture supernatants were measured. RESULTS: RU-486 decreased the number of implantation sites in the uterus of rats; however, the decrease was significantly alleviated by TSS (3%-diet), which tended to increase plasma progesterone. In rats with RU-486-induced implantation failure, endometrial gland LIF mRNA and endometrial LIF protein were markedly decreased while the gene expression of both decidualization-related factors such as interleukin-11, insulin-like growth factor binding protein-1, and cyclooxygenase-2, and progesterone responsive-related factors such as FK506 binding protein 5, were significantly decreased. These changes in the uterus of rats with implantation failure were significantly alleviated by TSS (3%-diet). Additionally, TSS significantly enhanced LIF protein production and LIF mRNA in Ishikawa cells. CONCLUSIONS: The mechanism whereby TSS ameliorates RU-486-induced implantation failure in rats may involve the alleviation of decreased LIF production derived from the endometrial gland, and a dysfunction of decidualization, including lower progesterone responsiveness in the model. These findings may partly contribute to the interpretation of the beneficial effects of TSS on infertility.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Implantação do Embrião/efeitos dos fármacos , Infertilidade Feminina/tratamento farmacológico , Fator Inibidor de Leucemia/metabolismo , Animais , Cromatografia Líquida , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Feminino , Masculino , Mifepristona , Progesterona/metabolismo , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem , Útero/efeitos dos fármacos , Útero/metabolismo
9.
Toxicol Mech Methods ; 31(1): 43-52, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32967526

RESUMO

Early detection and treatment of endometrial hyperplasia (EH) is mandatory for endometrial cancer prevention. Several bioactive agents of plant origin have been shown to elicit their chemotherapeutic effect against tumors and cancer via induction of mitochondrial permeability transition(mPT) pore opening. This research was therefore aimed at evaluating the potential chemopreventive effect of methyl palmitate (MP), on estradiol benzoate(EB)-induced EH, looking at the mitochondrial-mediated pathway and other possible mechanisms of action. Mitochondria were isolated using differential centrifugation. The mPT pore, mitochondrial ATPase (mATPase) activity, lipid peroxidation and cytochrome c release were determined by standard methods using spectrophotometer. Uterine interleukin 1b, MDA levels and SOD, GSH activities, were determined using commercially available kits. The uterine histological and immunohistochemical assessment of estrogen receptor (ERα), IL-1b and caspas-3 were carried out. The fibroblast cell count density was determined using histomorphometry. At all the concentrations of MP used, there was no significant induction of mPT pore opening, neither any enhancement of mATPase activity nor release of cytochrome c when compared to the control. Similar pattern of results were recorded for the in vivo study. However, there was marked increase in the uterine MDA and interleukin 1b levels, with concurrent decrease in SOD and GSH activities, in the EB-treated group, which was significantly reversed by MP co-administration. Endometrial Hyperplasia observed in the EB-treated group was ameliorated by MP co-administration. The immunoexpression of ERα and IL-1b in the EB-treated group was reversed by MP co-administration. This study suggests anti-inflammatory, antioxidant and anti-proliferative potential of MP against EB-induced EH.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Hiperplasia Endometrial/prevenção & controle , Endométrio/efeitos dos fármacos , Estradiol/análogos & derivados , Mitocôndrias/efeitos dos fármacos , Palmitatos/farmacologia , Animais , Citocromos c/metabolismo , Hiperplasia Endometrial/induzido quimicamente , Hiperplasia Endometrial/metabolismo , Hiperplasia Endometrial/patologia , Endométrio/metabolismo , Endométrio/patologia , Estradiol/toxicidade , Receptor alfa de Estrogênio/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Interleucina-1beta/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais
10.
Zhonghua Fu Chan Ke Za Zhi ; 55(12): 857-864, 2020 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-33355761

RESUMO

Objective: To analyze the pregnancy outcome, influencing factors and recurrence of fertility-preserving therapy for women with atypical endometrial hyperplasia (AEH) or endometrial carcinoma (EC). Methods: The multi-center retrospective study included 107 women with AEH or EC for fertility-preserving therapy in 10 hospitals from January 1st, 2009 to December 31st, 2018. The clinical pregnancy rate, live birth rate and recurrence of 66 patients with urgent child-bearing requirements after fertility-preserving treatment were analyzed. Results: (1) Among the 66 AEH and EC women with urgent child bearing requirements, 24 women chose spontaneous pregnancy, the clinical pregnancy rate was 54.2% (13/24) and the live birth rate was 41.7% (10/24), the median time from fertility-preserving therapy withdrawal to clinical pregnancy was 5.5 months. Forty-two women chose assisted reproductive technology (ART), the clinical pregnancy rate was 59.5% (25/42) and the live birth rate was 35.7% (15/42), the median time from fertility-preserving therapy withdrawal to clinical pregnancy was 19.5 months. The time from fertility-preserving therapy withdrawal to pregnancy in women receiving ART was significantly longer than that in women with spontaneous pregnancy (P=0.048). (2) Age and intrauterine adhesions were independent factors affecting the clinical pregnancy rate (P<0.05). (3) Among 107 patients with AEH or EC, the recurrence rate was 27.1% (29/107). Among the 42 cases who chose ART, 9 of them recurred before ART treatment, who received the fertility-preserving therapy again and then ART treatment, 8 women got clinical pregnancy,5 of them delivered at least a live birth. Conclusions: Women with AEH or EC could achieved satisfactory clinical pregnancy rate and live birth rate after fertility-preserving therapy. Age and intrauterine adhesions are independent factors affecting clinical pregnancy rate. The women with recurrent AEH or EC could be treated with fertility-preserving therapy again and get a satisfactory pregnancy outcome.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Hiperplasia Endometrial/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Preservação da Fertilidade , Tratamentos com Preservação do Órgão , Resultado da Gravidez/epidemiologia , Adulto , Antineoplásicos Hormonais/administração & dosagem , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/patologia , Endométrio/efeitos dos fármacos , Endométrio/patologia , Feminino , Fertilidade , Humanos , Nascido Vivo , Recidiva Local de Neoplasia , Gravidez , Taxa de Gravidez , Técnicas de Reprodução Assistida , Estudos Retrospectivos , Resultado do Tratamento
11.
Cochrane Database Syst Rev ; 10: CD006359, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33112418

RESUMO

BACKGROUND: A frozen embryo transfer (FET) cycle is when one or more embryos (frozen during a previous treatment cycle) are thawed and transferred to the uterus. Some women undergo fresh embryo transfer (ET) cycles with embryos derived from donated oocytes. In both situations, the endometrium is primed with oestrogen and progestogen in different doses and routes of administration. OBJECTIVES: To evaluate the most effective endometrial preparation for women undergoing transfer with frozen embryos or embryos from donor oocytes with regard to the subsequent live birth rate (LBR). SEARCH METHODS: The Cochrane Gynaecology and Fertility Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, LILACS, trials registers and abstracts of reproductive societies' meetings were searched in June 2020 together with reference checking and contact with study authors and experts in the field to identify additional studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. We analysed all available interventions versus placebo, no treatment, or between each other. The primary review outcome was live birth rate. Secondary outcomes were clinical and multiple pregnancy, miscarriage, cycle cancellation, endometrial thickness and adverse effects. MAIN RESULTS: Thirty-one RCTs (5426 women) were included. Evidence was moderate to very low-quality: the main limitations were serious risk of bias due to poor reporting of methods, and serious imprecision. Stimulated versus programmed cycle We are uncertain whether a letrozole-stimulated cycle compared to a programmed cycle, for endometrial preparation, improves LBR (odds ratio (OR) 1.26, 95% confidence interval (CI) 0.49 to 3.26; 100 participants; one study; very low-quality evidence). Stimulating with follicle stimulating hormone (FSH), letrozole or clomiphene citrate may improve clinical pregnancy rate (CPR) (OR 1.63, 95% CI 1.12 to 2.38; 656 participants; five studies; I2 = 11%; low-quality evidence). We are uncertain if they reduce miscarriage rate (MR) (OR 0.79, 95% CI 0.36 to 1.71; 355 participants; three studies; I2 = 0%; very low-quality evidence). Endometrial thickness (ET) may be reduced with clomiphene citrate (mean difference(MD) -1.04, 95% CI -1.59 to -0.49; 92 participants; one study; low-quality evidence). Other outcomes were not reported. Natural versus programmed cycle We are uncertain of the effect from a natural versus programmed cycle for LBR (OR 0.97, 95% CI 0.74 to 1.28; 1285 participants; four studies; I2 = 0%; very low-quality evidence) and CPR (OR 0.79, 95% CI 0.62 to 1.01; 1249 participants; five studies; I2 = 60%; very low-quality evidence), while a natural cycle probably reduces the cycle cancellation rate (CCR) (OR 0.60, 95% CI 0.44 to 0.82; 734 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and ET. No study reported other outcomes. Transdermal versus oral oestrogens From low-quality evidence we are uncertain of the effect transdermal compared to oral oestrogens has on CPR (OR 0.86, 95% CI 0.59 to 1.25; 504 participants; three studies; I2 = 58%) or MR (OR 0.55, 95% CI 0.27 to 1.09; 414 participants; two studies; I2 = 0%). Other outcomes were not reported. Day of starting administration of progestogen When doing a fresh ET using donated oocytes in a synchronised cycle starting progestogen on the day of oocyte pick-up (OPU) or the day after OPU, in comparison with recipients that start progestogen the day prior to OPU, probably increases the CPR (OR 1.87, 95% CI 1.13 to 3.08; 282 participants; one study, moderate-quality evidence). We are uncertain of the effect on multiple pregnancy rate (MPR) or MR. It probably reduces the CCR (OR 0.28, 95% CI 0.11 to 0.74; 282 participants; one study; moderate-quality evidence). No study reported other outcomes. Gonadotropin-releasing hormone (GnRH) agonist versus control A cycle with GnRH agonist compared to without may improve LBR (OR 2.62, 95% CI 1.19 to 5.78; 234 participants; one study; low-quality evidence). From low-quality evidence we are uncertain of the effect on CPR (OR 1.08, 95% CI 0.82 to 1.43; 1289 participants; eight studies; I2 = 20%), MR (OR 0.85, 95% CI 0.36 to 2.00; 828 participants; four studies; I2 = 0%), CCR (OR 0.49, 95% CI 0.21 to 1.17; 530 participants; two studies; I2 = 0%) and ET (MD -0.08, 95% CI -0.33 to 0.16; 697 participants; four studies; I2 = 4%). No study reported other outcomes. Among different GnRH agonists From very low-quality evidence we are uncertain if cycles among different GnRH agonists improves CPR or MR. No study reported other outcomes. GnRH agonists versus GnRH antagonists GnRH antagonists compared to agonists probably improves CPR (OR 0.62, 95% CI 0.42 to 0.90; 473 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and MPR. No study reported other outcomes. Aspirin versus control From very low-quality evidence we are uncertain whether a cycle with aspirin versus without improves LBR, CPR, or ET. Steroids versus control From very low-quality evidence we are uncertain whether a cycle with steroids compared to without improves LBR, CPR or MR. No study reported other outcomes. AUTHORS' CONCLUSIONS: There is insufficient evidence on the use of any particular intervention for endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers. In frozen embryo transfers, low-quality evidence showed that clinical pregnancy rates may be improved in a stimulated cycle compared to a programmed one, and we are uncertain of the effect when comparing a programmed cycle to a natural cycle. Cycle cancellation rates are probably reduced in a natural cycle. Although administering a GnRH agonist, compared to without, may improve live birth rates, clinical pregnancy rates will probably be improved in a GnRH antagonist cycle over an agonist cycle. In fresh synchronised oocyte donor cycles, the clinical pregnancy rate is probably improved and cycle cancellation rates are probably reduced when starting progestogen the day of or day after donor oocyte retrieval. Adequately powered studies are needed to evaluate each treatment more accurately.


Assuntos
Criopreservação , Transferência Embrionária/métodos , Embrião de Mamíferos , Endométrio/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/agonistas , Doação de Oócitos , Aborto Espontâneo/epidemiologia , Viés , Clomifeno/administração & dosagem , Esquema de Medicação , Implantação do Embrião/fisiologia , Endométrio/fisiologia , Feminino , Hormônio Foliculoestimulante/administração & dosagem , Humanos , Letrozol/administração & dosagem , Nascido Vivo/epidemiologia , Gravidez , Taxa de Gravidez , Progesterona/administração & dosagem , Progestinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Life Sci ; 260: 118439, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32950574

RESUMO

AIMS: This study aims to investigate the effects of intrauterine perfusion of granulocyte colony-stimulating factor (G-CSF) on a thin-endometrium rat model. MAIN METHODS: Twenty rats in two groups of 10 were used. Group I was perfused with normal saline (NS) in the right uterine horn and 95% ethanol in the left one. Group II was bilaterally perfused with 95% ethanol into the uterine horns. After three estrous cycles, Group II was perfused with NS in the right uterine horn and G-CSF (30 µg/kg) in the left one. Hematoxylin-eosin (HE) and immunohistochemistry (IHC) staining were used to detect changes in endometrial thickness and expression of cytokeratin 19 (CK19) and vimentin (Vim). The relative expression levels of vascular endothelial growth factor (Vegf) and leukemia inhibitory factor (Lif) were also tested via reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and Western-blot analyses. KEY FINDINGS: G-CSF treatment significantly increased the thickness of the endometrium in the 95% ethanol-induced thin-endometrium rat model. The expression levels of endometrial glandular epithelial cell marker for CK19 and stromal cell marker Vim were augmented in the G-CSF-treated group compared with the control group. Moreover, G-CSF treatment stimulated the expression of VEGF and LIF in the 95% ethanol-induced thin-endometrium rat model. SIGNIFICANCE: G-CSF intrauterine perfusion improved endometrial receptivity in the thin-endometrium rat model by stimulating endometrial proliferation and angiogenesis.


Assuntos
Endométrio/efeitos dos fármacos , Endométrio/fisiopatologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Animais , Endométrio/fisiologia , Etanol/toxicidade , Feminino , Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Inibidor de Leucemia/genética , Perfusão , Ratos Sprague-Dawley , Útero/fisiologia , Fator A de Crescimento do Endotélio Vascular/genética , Vimentina/metabolismo
13.
Am J Surg Pathol ; 44(10): 1429-1439, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32931681

RESUMO

BACKGROUND: Conservative management with progestin is a treatment option for atypical hyperplasia (AH). However, pathologic diagnosis of residual/recurrent lesions is often problematic because of the profound morphologic changes induced by progestin and the lack of established diagnostic criteria for progestin-treated residual AH. METHODS: We conducted a longitudinal study of 265 endometrial biopsies from 54 patients with a history of AH on progestin therapy. Patient outcomes were divided into 3 categories after morphologic review and immunohistochemical staining with phosphatase and tensin homolog (PTEN) and paired box 2 (PAX2): (1) persistent or residual disease; (2) recurrent disease; (3) complete response. All specimens were classified into 3 categories based on morphology: (1) persistent/recurrent disease (nonresponse), (2) morphologically uncertain response, (3) optimally treated (complete response). The staining patterns of PTEN/PAX2 were tracked over time in individual patients and correlated with morphologic findings before and after progestin therapy. RESULTS: Our data showed that aberrant expression patterns of PTEN and/or PAX2 were identified in 48 (88.9%) of the 54 primary biopsies and persisted in persistent/recurrent AH across serial endometrial biopsies (n=99, P<0.00001), while normal PTEN and PAX2 expressions were consistently observed in optimally treated cases (n=84, P<0.00001). More importantly, follow-up biopsies that showed a morphologically uncertain response but a PTEN/PAX2 expression pattern identical to the initial biopsy were significantly correlated with persistent or recurrent disease (n=18, P=0.000182), as evidenced by areas with morphologic features diagnostic of AH on subsequent biopsy. CONCLUSIONS: Biomarker PTEN/PAX2 signatures offer a valuable diagnostic aid to identify residual AH in progestin-treated endometrial samples for which the biomarker status from preprogestin treated AH is known. The findings of this study are promising for a possible future change of diagnostic practice.


Assuntos
Biomarcadores Tumorais/análise , Hiperplasia Endometrial/diagnóstico , Hiperplasia Endometrial/tratamento farmacológico , Endométrio/efeitos dos fármacos , Congêneres da Progesterona/uso terapêutico , Adulto , Idoso , Biomarcadores/análise , Endométrio/patologia , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Fator de Transcrição PAX2/análise , PTEN Fosfo-Hidrolase/análise , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/tratamento farmacológico , Recidiva
14.
Womens Health (Lond) ; 16: 1745506520952003, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32833600

RESUMO

Administration of Dienogest prior to hysteroscopic polypectomy is empirically performed, but the physiological effects of Dienogest on endometrial polyps are unclear. We aimed to investigate the effects of Dienogest on the proliferation and inflammation of endometrial polyps. We conducted a retrospective case study on 40 menstruating women who underwent hysteroscopic polypectomy at our hospital. We collected clinical data, and the polyps were divided by morphological appearance. The specimens obtained were immunostained for Ki67 as a marker of cellar proliferation and CD138 as a marker of plasmacytes, which are a hallmark of chronic endometritis. Dienogest significantly suppressed the proliferation status of EPs because Dienogest treatment prior to the operation significantly reduced the Ki67 index (41.25 ± 16.85 vs 7.18 ± 9.82, p < 0.01). We found that sessile-type polyps showed a significantly lower Ki67 index than the pedunculated type (12.28 ± 11.12 vs 2.09 ± 2.73, p = 0.026). The presence of CD138-positive cells was more pronounced in sessile-type polyps than in pedunculated polyps (p = 0.018). However, Dienogest treatment showed no apparent effect on inflammation status, as detected by CD138-positive cells. We revealed that Dienogest suppressed cellular proliferation, and morphological classification of endometrial polyps could be used to predict the responsiveness to Dienogest. However, Dienogest might not affect cellular inflammation.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Endométrio/efeitos dos fármacos , Nandrolona/análogos & derivados , Pólipos/tratamento farmacológico , Adulto , Endométrio/patologia , Feminino , Humanos , Histeroscopia , Pessoa de Meia-Idade , Nandrolona/uso terapêutico , Estudos Retrospectivos , Doenças Uterinas/patologia
15.
Hum Reprod ; 35(8): 1781-1796, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32712670

RESUMO

STUDY QUESTION: Does HIV protease inhibitor (PI)-based combination antiretroviral therapy (cART) initiated at periconception affect key events in early pregnancy, i.e. decidualization and spiral artery remodeling? SUMMARY ANSWER: Two PIs, lopinavir and darunavir, currently offered as cART options in HIV-positive pregnancies were evaluated, and we found that lopinavir-based cART, but not darunavir-based cART, impaired uterine decidualization and spiral artery remodeling in both human ex vivo and mouse in vivo experimental models. WHAT IS KNOWN ALREADY: Early initiation of cART is recommended for pregnant women living with HIV. However, poor birth outcomes are frequently observed in HIV-positive pregnancies exposed to PI-based cART, especially when it is initiated prior to conception. The correlation between early initiation of PI-cART and adverse birth outcomes is poorly understood, due to lack of data on the specific effects of PI-cART on the early stages of pregnancy involving uterine decidualization and spiral artery remodeling. STUDY DESIGN, SIZE, DURATION: Lopinavir and darunavir were evaluated in clinically relevant combinations using an ex vivo human first-trimester placenta-decidua explant model, an in vitro human primary decidual cell culture system, and an in vivo mouse pregnancy model. The first-trimester (gestational age, 6-8 weeks) human placenta-decidua tissue was obtained from 11 to 15 healthy women undergoing elective termination of pregnancy. C57Bl/6 female mice (four/treatment group) were administered either lopinavir-cART, darunavir-cART or water by oral gavage once daily starting on the day of plug detection until sacrifice. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human: Spiral artery remodeling was assessed by immunohistochemical analysis of first-trimester placenta-decidua explant co-culture system. Trophoblast migration was measured using a placental explant culture. A primary decidual cell culture was used to evaluate the viability of immune cell populations by flow cytometry. Soluble factors, including biomarkers of decidualization and angiogenesis, were quantified by ELISA and Luminex assay using decidua-conditioned media. Mouse: In the mouse pregnancy model, gestational day 6.5 or 9.5 implantation sites were used to assess decidualization, spiral artery remodeling and uterine natural killer (uNK) cell numbers by immunohistochemistry. Transcription factor STAT3 was assayed by immunohistochemistry in both human decidua and mouse implantation sites. MAIN RESULTS AND THE ROLE OF CHANCE: Lopinavir-cART, but not darunavir-cART, impaired uterine decidualization and spiral artery remodeling in both experimental models. Lopinavir-cART treatment was also associated with selective depletion of uNK cells, reduced trophoblast migration and defective placentation. The lopinavir-associated decidualization defects were attributed to a decrease in expression of transcription factor STAT3, known to regulate decidualization. Our results suggest that periconceptional initiation of lopinavir-cART, but not darunavir-cART, causes defective maturation of the uterine endometrium, leading to impairments in spiral artery remodeling and placentation, thus contributing to the poor birth outcomes. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The human first-trimester placenta/decidua samples could only be obtained from healthy females undergoing elective termination of pregnancy. As biopsy is the only way to obtain first-trimester decidua from pregnant women living with HIV on PI-cART, ethics approval and participant consent are difficult to obtain. Furthermore, our animal model is limited to the study of cART and does not include HIV. HIV infection is also associated with immune dysregulation, inflammation, alterations in angiogenic factors and complement activation, all of which could influence decidual and placental vascular remodeling and modify any cART effects. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide mechanistic insight with direct clinical implications, rationalizing why the highest adverse birth outcomes are reported in HIV-positive pregnancies exposed to lopinavir-cART from conception. We demonstrate that dysregulation of decidualization is the mechanism through which lopinavir-cART, but not darunavir-cART, use in early pregnancy leads to poor birth outcomes. Although lopinavir is no longer a first-line regimen in pregnancy, it remains an alternate regimen and is often the only PI available in low resource settings. Our results highlight the need for reconsidering current guidelines recommending lopinavir use in pregnancy and indicate that lopinavir should be avoided especially in the first trimester, whereas darunavir is safe to use and should be the preferred PI in pregnancy.Further, in current times of the COVID-19 pandemic, lopinavir is among the top drug candidates which are being repurposed for inclusion in clinical trials world-over, to assess their therapeutic potential against the dangerous respiratory disease. Current trials are also testing the efficacy of lopinavir given prophylactically to protect health care workers and people with potential exposures. Given the current extraordinary numbers, these might include women with early pregnancies, who may or may not be cognizant of their gestational status. This is a matter of concern as it could mean that women with early pregnancies might be exposed to this drug, which can cause decidualization defects. Our findings provide evidence of safety concerns surrounding lopinavir use in pregnancy, that women of reproductive age considering participation in such trials should be made aware of, so they can make a fully informed decision. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by funding from the Canadian Institutes of Health Research (CIHR) (PJT-148684 and MOP-130398 to L.S.). C.D. received support from CIHR Foundation (FDN143262 to Stephen Lye). S.K. received a TGHRI postdoctoral fellowship. The authors declare that there are no conflicts of interest. L.S. reports personal fees from ViiV Healthcare for participation in a Women and Transgender Think Tank.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Lopinavir/efeitos adversos , Placentação/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Animais , Betacoronavirus/efeitos dos fármacos , Células Cultivadas , Ensaios Clínicos como Assunto , Técnicas de Cocultura , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Darunavir/efeitos adversos , Decídua/irrigação sanguínea , Decídua/citologia , Decídua/efeitos dos fármacos , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Implantação do Embrião/efeitos dos fármacos , Endométrio/irrigação sanguínea , Endométrio/efeitos dos fármacos , Feminino , Humanos , Exposição Materna/efeitos adversos , Camundongos , Pandemias , Pneumonia Viral/virologia , Gravidez , Primeiro Trimestre da Gravidez/efeitos dos fármacos , Cultura Primária de Células , Trofoblastos , Remodelação Vascular/efeitos dos fármacos
16.
J Comput Assist Tomogr ; 44(4): 485-489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32558766

RESUMO

PURPOSE: To evaluate tamoxifen-related endometrial changes in premenopausal female patients with diffusion-weighted magnetic resonance imaging (DWI). METHODS: This prospective study was performed on 71 premenopausal female patients (mean age, 41 years) who were receiving tamoxifen therapy. All patients underwent magnetic resonance imaging with DWI of the pelvis and hysteroscopic-guided endometrial biopsy. The apparent diffusion coefficient (ADC) values of the endometrial plate were calculated and correlated with pathological results. RESULTS: The mean ADCs of tamoxifen-related benign endometrial lesions (1.35 ± 0.19 and 1.32 ± 0.13 × 10 mm/s) were significantly higher (P = 0.001) than those of normal endometrial plate (0.95 ± 0.11 and 0.93 ± 0.11 × 10 mm/s) by both reviewers, respectively. The cutoff ADC values used to differentiate tamoxifen-related benign endometrial lesions from normal endometrium were 1.07 and 1.02 × 10 mm/s with areas under the curve of 0.94 and 0.93 and accuracy of 94.4 and 95.8 by both reviewers, respectively. The mean ADC values of endometrial polyp (EP) (1.44 ± 0.19 and 1.42 ± 0.22 × 10 mm/s) were significantly higher (P = 0.001) than those of endometrial hyperplasia (EH) (1.25 ± 0.19 and 1.23 ± 0.19 × 10 mm/s) by both reviewers, respectively. The cutoff ADC values used to differentiate EP from EH were 1.38 × 10 and 1.36 × 10 mm/s with areas under the curve of 0.81 and 0.77 and accuracy of 80% and 70% by both reviewers, respectively. There was an insignificant difference in ADC value between typical and atypical EH. The ADC values of endometrial cancer (0.80 and 0.78 × 10 mm/s) were lower than those of tamoxifen-related benign endometrial lesions. The final diagnosis was normal endometrium (n = 36), benign endometrial lesions either EH (n = 17), or EP (n = 16), and endometrial cancer in only 2 patients. CONCLUSIONS: We concluded that DWI helps in detection and characterization of different tamoxifen-related endometrial changes in the premenopausal female patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Hiperplasia Endometrial/diagnóstico por imagem , Neoplasias do Endométrio/diagnóstico por imagem , Endométrio/efeitos dos fármacos , Tamoxifeno/efeitos adversos , Adulto , Imagem de Difusão por Ressonância Magnética , Hiperplasia Endometrial/induzido quimicamente , Neoplasias do Endométrio/induzido quimicamente , Endométrio/diagnóstico por imagem , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Pessoa de Meia-Idade , Variações Dependentes do Observador , Pré-Menopausa , Estudos Prospectivos , Tamoxifeno/uso terapêutico
17.
PLoS Genet ; 16(6): e1008601, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32555663

RESUMO

Programmed cellular responses to cycling ovarian-derived steroid hormones are central to normal endometrial function. Abnormalities therein, as in the estrogen-dependent, progesterone-"resistant" disorder, endometriosis, predispose to infertility and poor pregnancy outcomes. The endometrial stromal fibroblast (eSF) is a master regulator of pregnancy success. However, the complex hormone-epigenome-transcriptome interplay in eSF by each individual steroid hormone, estradiol (E2) and/or progesterone (P4), under physiologic and pathophysiologic conditions, is poorly understood and was investigated herein. Genome-wide analysis in normal, early and late stage eutopic eSF revealed: i) In contrast to P4, E2 extensively affected the eSF DNA methylome and transcriptome. Importantly, E2 resulted in a more open versus closed chromatin, confirmed by histone modification analysis. Combined E2 with P4 affected a totally different landscape than E2 or P4 alone. ii) P4 responses were aberrant in early and late stage endometriosis, and mapping differentially methylated CpG sites with progesterone receptor targets from the literature revealed different but not decreased P4-targets, leading to question the P4-"resistant" phenotype in endometriosis. Interestingly, an aberrant E2-response was noted in eSF from endometriosis women; iii) Steroid hormones affected specific genomic contexts and locations, significantly enriching enhancers and intergenic regions and minimally involving proximal promoters and CpG islands, regardless of hormone type and eSF disease state. iv) In eSF from women with endometriosis, aberrant hormone-induced methylation signatures were mainly due to existing DNA methylation marks prior to hormone treatments and involved known endometriosis genes and pathways. v) Distinct DNA methylation and transcriptomic signatures revealed early and late stage endometriosis comprise unique disease subtypes. Taken together, the data herein, for the first time, provide significant insight into the hormone-epigenome-transcriptome interplay of each steroid hormone in normal eSF, and aberrant E2 response, distinct disease subtypes, and pre-existing epigenetic aberrancies in the setting of endometriosis, provide mechanistic insights into how endometriosis affects endometrial function/dysfunction.


Assuntos
Metilação de DNA , Endometriose/genética , Epigênese Genética , Estradiol/metabolismo , Progesterona/metabolismo , Transcriptoma , Adulto , Cromatina/genética , Cromatina/metabolismo , Ilhas de CpG , Endometriose/metabolismo , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Estradiol/farmacologia , Feminino , Humanos , Progesterona/farmacologia
18.
Adv Exp Med Biol ; 1242: 145-177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32406032

RESUMO

The uterus and especially the endometrium are sensitive targets for steroid sex hormones, capable to modify structure and function with promptitude and versatility in order to secure reproductive functions. Hormone therapy is used to counteract deprivation, abnormal, and deleterious functions of "natural" hormones. It is widely prescribed, being used by millions of women all over the world. It seems that most women would use at least some hormone therapy at some point of their life, as contraceptives, ovarian stimulation, replacement therapy, or hormone antitumoral therapy. The diagnosis of uterine tissue, mostly of the frequently performed endometrial biopsies taken from women undergoing hormone therapy, is often confusing and difficult to interpret due to the complexity of histologic changes. Permanently changing hormonal pharmaceutical products, regimens, dosages, as well as new concepts of therapy are challenges for both users and medical prescribers. This chapter addresses the most commonly issues arising from the gynecological pathology interpretation of hormonal therapy effects on the uterus.


Assuntos
Hormônios Esteroides Gonadais/farmacologia , Terapia de Reposição Hormonal , Útero/efeitos dos fármacos , Biópsia , Endométrio/efeitos dos fármacos , Feminino , Hormônios Esteroides Gonadais/metabolismo , Humanos
19.
Artigo em Inglês | MEDLINE | ID: mdl-32235321

RESUMO

Testosterone could have adverse effect on fertility. In this study, we hypothesized that this hormone could reduce the number of embryo implantations via affecting the normal endometrium ultrastructure and expression of endometrial proteins involved in implantation. Therefore, the aims were to identify these adverse testosterone effects. METHODS: Intact pregnant rats were given 250 or 500 µg/kg/day testosterone for three days, beginning from day 1 of pregnancy. Rats were euthanized either at day 4 to analyze the ultra-structural changes in the endometrium and expression and distribution of MECA-79 protein, or at day 6 to determine the number of implantation sites. RESULTS: Administration of 500 µg/kg/day testosterone suppresses endometrial pinopodes development and down-regulates expression and distribution of MECA-79 protein in the uterus. In addition, the number of implantation sites were markedly decreased. CONCLUSIONS: Changes in endometrial ultrastructure and expression of implantation protein in the endometrium in early pregnancy period could be the reason for failure of embryo implantation under testosterone influence.


Assuntos
Antígenos de Superfície/metabolismo , Implantação do Embrião/efeitos dos fármacos , Endométrio/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Testosterona/administração & dosagem , Animais , Endométrio/ultraestrutura , Feminino , Selectina L , Gravidez , Ratos
20.
Int J Gynaecol Obstet ; 150(1): 77-82, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32293031

RESUMO

OBJECTIVE: To evaluate differences in Doppler parameters and pregnancy outcomes, if any, and to determine the predictive accuracy of such indices, as well as the effects of low-dose aspirin (LDA) in unexplained recurrent pregnancy loss (URPL). METHODS: An observational study was conducted at Ren Ji Hospital, Shanghai, China, from May 2015 to December 2016. The endometrial thickness, and the pulsatility index (PI), resistive index (RI), and systolic-to-diastolic ratio (S/D) values of endometrial and uterine artery blood flow were collected. Receiver operating characteristic (ROC) curve analysis was used to analyze data from URPL patients (three or more first-trimester spontaneous abortions with unknown etiology) and patients with normal fertility. A second ultrasonography examination was performed in URPL patients who had received daily LDA for 2 months. RESULTS: There were 190 URPL patients and 35 control patients. Endometrial thickness was significantly thinner in URPL patients than control patients (P=0.005). The PI, RI, and S/D values for endometrial blood flow and the mean PI, RI, and S/D values for uterine arteries were significantly higher in URPL patients (P<0.001). The predictive accuracy of the indices mentioned above were 0.660, 0.802, 0.852, 0.837, 0.784, 0.929, and 0.929, respectively. Following LDA supplementation, URPL patients showed a significant reduction in resistance to endometrial and uterine artery blood flow (P<0.001). CONCLUSION: URPL patients had impaired uterine perfusion. Doppler parameters are valuable in predicting women at high risk of URPL. LDA could be effective in improving endometrial receptivity.


Assuntos
Aborto Habitual/fisiopatologia , Aspirina/farmacologia , Endométrio/efeitos dos fármacos , Aborto Habitual/prevenção & controle , Adulto , Aspirina/administração & dosagem , Estudos de Casos e Controles , China , Endométrio/irrigação sanguínea , Endométrio/diagnóstico por imagem , Feminino , Humanos , Gravidez , Curva ROC , Ultrassonografia Doppler , Artéria Uterina/diagnóstico por imagem , Artéria Uterina/efeitos dos fármacos
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