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1.
Arterioscler Thromb Vasc Biol ; 40(9): 2143-2158, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640903

RESUMO

OBJECTIVE: ERα (estrogen receptor alpha) exerts nuclear genomic actions and also rapid membrane-initiated steroid signaling. The mutation of the cysteine 451 into alanine in vivo has recently revealed the key role of this ERα palmitoylation site on some vasculoprotective actions of 17ß-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ERα which has also been described to be involved in its E2-induced rapid signaling with PI-3K (phosphoinositide 3-kinase) as well as G protein in cultured cell lines. Approach and Results: We generated a mouse model harboring a point mutation of the murine counterpart of this arginine into alanine (R264A-ERα). In contrast to the C451A-ERα, the R264A-ERα females are fertile with standard hormonal serum levels and normal control of hypothalamus-pituitary ovarian axis. Although R264A-ERα protein abundance was normal, the well-described membrane ERα-dependent actions of estradiol, such as the rapid dilation of mesenteric arteries and the acceleration of endothelial repair of carotid, were abrogated in R264A-ERα mice. In striking contrast, E2-regulated gene expression was highly preserved in the uterus and the aorta, revealing intact nuclear/genomic actions in response to E2. Consistently, 2 recognized nuclear ERα-dependent actions of E2, namely atheroma prevention and flow-mediated arterial remodeling were totally preserved. CONCLUSIONS: These data underline the exquisite role of arginine 264 of ERα for endothelial membrane-initiated steroid signaling effects of E2 but not for nuclear/genomic actions. This provides the first model of fertile mouse with no overt endocrine abnormalities with specific loss-of-function of rapid ERα signaling in vascular functions.


Assuntos
Lesões das Artérias Carótidas/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Terapia de Reposição de Estrogênios , Estrogênios/farmacologia , Fertilidade/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Mutação Puntual , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Endotélio Vascular/lesões , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Ativação Enzimática , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Ciclo Estral/efeitos dos fármacos , Feminino , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III/metabolismo , Ovariectomia , Reepitelização/efeitos dos fármacos , Transdução de Sinais , Fatores de Tempo , Útero/efeitos dos fármacos , Útero/metabolismo , Remodelação Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
2.
Medicine (Baltimore) ; 99(22): e20421, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481439

RESUMO

To evaluate the efficacy and feasibility of levonorgestrel-releasing intrauterine device (LNG-IUD) use longer than 5 years in women with adenomyosis.Data were retrospectively collected from patients who were treated with LNG-IUD longer than 5 years at the Chungnam National University hospital for adenomyosis diagnosed with ultrasonography from January 2006 to November 2013.A total of 131 patients who were diagnosed with adenomyosis had treated with LNG-IUD longer than 5 years. The mean duration of keeping 1 device without replacement was 58.35 ±â€Š15.98 months, and total duration of LNG-IUD treatment was 83.86 ±â€Š23.88 months. A total of 51 patients stopped using LNG-IUD after 5 years and the mean age at the time of LNG-IUD removal was 52.46 ±â€Š6.9. LNG-IUD treatment had a significant effect on both menorrhagia and dysmenorrhea starting from the first month of insertion (P < .01), which persisted until 6 years when the effect started to plateau. The decrease in uterine volume was not consistent during the treatment period. The uterine volume decreased significantly only in the first and second year of LNG-IUD treatment and then from eighth to tenth year of LNG-IUD treatment (P < .05). Adverse events after insertion of LNG-IUD decreased significantly after 5 years.LNG-IUD treatment longer than 5 years is an effective and feasible method for patients diagnosed with adenomyosis.


Assuntos
Adenomiose/tratamento farmacológico , Contraceptivos Hormonais/administração & dosagem , Dispositivos Intrauterinos Medicados , Levanogestrel/administração & dosagem , Adenomiose/patologia , Adulto , Contraceptivos Hormonais/efeitos adversos , Estudos de Viabilidade , Feminino , Humanos , Dispositivos Intrauterinos Medicados/efeitos adversos , Levanogestrel/efeitos adversos , Menorragia/tratamento farmacológico , Pessoa de Meia-Idade , Tamanho do Órgão , Manejo da Dor , Estudos Retrospectivos , Fatores de Tempo , Útero/efeitos dos fármacos , Útero/patologia
3.
Ecotoxicol Environ Saf ; 199: 110675, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32402895

RESUMO

An oral painless dietary therapy is also indispensable in the management of arsenic toxicity despite of its conventional painful therapeutic management. The present study focused on the management of arsenic mediated female reproductive dysfunctions by dietary therapy of N-acetyl cysteine (NAC). Here, sodium arsenite was given at the dose of 10 mg/kg body weight orally for the first 8 day. Day 9 onwards up to day 16 these arsenicated rats were provided with NAC (250 mg/kg body weight) enriched basal diet once daily. Arsenic intoxicated group exhibited a comparable inactivation of antioxidant enzymes superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) due to oxidative stress in reproductive organs along with a simultaneous elevation of lipid peroxidation state and decline in non-protein soluble thiols (NPSH) level in female reproductive organs. Arsenic intoxication also accomplished with the up-regulation of inflammatory markers tumour necrosis factor (TNF α) and nuclear factor κB (NF κB). Pro-apoptotic Bax gene and p53 gene expressions were also raised due to arsenic intoxication while anti-apoptotic Bcl-2 gene expression was suppressed. In fact, arsenication decreased the circulating level of vitamin B12 and folic acid. Dietary NAC supplementation significantly reversed back the activity of antioxidant enzymes in arsenite fed rats towards normalcy and also sustained the normal reproductive cyclicity, utero-ovarian histo-morphology and estradiol receptor α (ER-α) expression in these reproductive organs. Dietary NAC exerted its positive action against arsenic intoxication by up-regulation of Bcl-2 gene expression along with the suppression of pro-apoptotic Bax gene and p53 gene. Thus, dietary NAC also plays anti-apoptotic, anti-inflammatory, and anti-oxidative role against arsenic toxicity. NAC also regulates the components (vitamin B12 and folic acid) of S-adenosylmethionine pool in the way of probable removal of arsenic from the system.


Assuntos
Acetilcisteína/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Arsenitos/toxicidade , Expressão Gênica/efeitos dos fármacos , Ovário/efeitos dos fármacos , Útero/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Apoptose/genética , Suplementos Nutricionais , Feminino , Masculino , Ovário/metabolismo , Ovário/patologia , Ovário/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Útero/metabolismo , Útero/patologia , Útero/fisiopatologia
4.
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
5.
Environ Health Perspect ; 128(3): 37001, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32186404

RESUMO

BACKGROUND: Embryo implantation relies on precise hormonal regulation, associated gene expression changes, and appropriate female reproductive tract tissue architecture. Female mice exposed neonatally to the phytoestrogen genistein (GEN) at doses similar to those in infants consuming soy-based infant formulas are infertile due in part to uterine implantation defects. OBJECTIVES: Our goal was to determine the mechanisms by which neonatal GEN exposure causes implantation defects. METHODS: Female mice were exposed to GEN on postnatal days (PND)1-5 and uterine tissues collected on PND5, PND22-26, and during pregnancy. Analysis of tissue weights, morphology, and gene expression was performed using standard histology, confocal imaging with three-dimensional analysis, real-time reverse transcription polymerase chain reaction (real-time RT-PCR), and microarrays. The response of ovariectomized adults to 17ß-estradiol (E2) and artificial decidualization were measured. Leukemia inhibitory factor (LIF) injections were given intraperitoneally and implantation sites visualized. Gene expression patterns were compared with curated data sets to identify upstream regulators. RESULTS: GEN-exposed mice exhibited reduced uterine weight gain in response to E2 treatment or artificial decidualization compared with controls; however, expression of select hormone responsive genes remained similar between the two groups. Uteri from pregnant GEN-exposed mice were posteriorized and had reduced glandular epithelium. Implantation failure was not rescued by LIF administration. Microarray analysis of GEN-exposed uteri during early pregnancy revealed significant overlap with several conditional uterine knockout mouse models, including Foxa2, Wnt4, and Sox17. These models exhibit reduced endometrial glands, features of posteriorization and implantation failure. Expression of Foxa2, Wnt4, and Sox17, as well as genes important for neonatal uterine differentiation (Wnt7a, Hoxa10, and Msx2), were severely disrupted on PND5 in GEN-exposed mice. DISCUSSION: Our findings suggest that neonatal GEN exposure in mice disrupts expression of genes important for uterine development, causing posteriorization and diminished gland function during pregnancy that contribute to implantation failure. These findings could have implications for women who consumed soy-based formulas as infants. https://doi.org/10.1289/EHP6336.


Assuntos
Implantação do Embrião/efeitos dos fármacos , Genisteína/efeitos adversos , Fitoestrógenos/efeitos adversos , Útero/efeitos dos fármacos , Animais , Feminino , Camundongos , Gravidez , Útero/crescimento & desenvolvimento , Útero/fisiopatologia
6.
Am J Physiol Endocrinol Metab ; 318(5): E646-E654, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32125882

RESUMO

Mouse models with lifelong inactivation of estrogen receptor-α (ERα) show that ERα is the main mediator of estrogenic effects in bone, thymus, uterus, and fat. However, ERα inactivation early in life may cause developmental effects that confound the adult phenotypes. To address the specific role of adult ERα expression for estrogenic effects in bone and other nonskeletal tissues, we established a tamoxifen-inducible ERα-inactivated model by crossing CAGG-Cre-ER and ERαflox/flox mice. Tamoxifen-induced ERα inactivation after sexual maturation substantially reduced ERα mRNA levels in cortical bone, trabecular bone, thymus, uterus, gonadal fat, and hypothalamus, in CAGG-Cre-ERαflox/flox (inducible ERαKO) compared with ERαflox/flox (control) mice. 17ß-estradiol (E2) treatment increased trabecular bone volume fraction (BV/TV), cortical bone area, and uterine weight, while it reduced thymus weight and fat mass in ovariectomized control mice. The estrogenic responses were substantially reduced in inducible ERαKO mice compared with control mice on BV/TV (-67%), uterine weight (-94%), thymus weight (-70%), and gonadal fat mass (-94%). In contrast, the estrogenic response on cortical bone area was unaffected in inducible ERαKO compared with control mice. In conclusion, using an inducible ERαKO model, not confounded by lack of ERα during development, we demonstrate that ERα expression in sexually mature female mice is required for normal E2 responses in most, but not all, tissues. The finding that cortical, but not trabecular bone, responds normally to E2 treatment in inducible ERαKO mice strengthens the idea of cortical and trabecular bone being regulated by estrogen via different mechanisms.


Assuntos
Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Útero/efeitos dos fármacos , Animais , Osso e Ossos/metabolismo , Receptor alfa de Estrogênio/genética , Feminino , Camundongos , Camundongos Transgênicos , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Timo/efeitos dos fármacos , Timo/metabolismo , Útero/metabolismo
7.
J Pharmacol Exp Ther ; 373(3): 381-390, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32205366

RESUMO

Prostaglandin (PG) E analogs are used clinically to ripen the cervix and induce labor. However, selective receptor agonists may have potential to improve induction response rates or manage unwanted uterine hypercontractility in conditions such as dysmenorrhea and preterm labor. To characterize their therapeutic value, PGE2 analogs were used to investigate the functional E-type prostanoid (EP) receptor population in isolated human uterus. Responsiveness in mouse tissues was also examined to validate its use as a preclinical model. Uterine samples were obtained from mice at dioestrus (n = 12), term gestation (n = 14), and labor (n = 12) and from the lower uterus of women undergoing hysterectomy (n = 12) or Caesarean section (n = 18). Vehicle and agonist effects were assessed using superfusion and immersion techniques. PGE2 evoked predominant excitatory responses in mouse and relaxation in human tissues. Selective EP4 agonists inhibited tissue activity in both nonpregnant species, while the EP2 mimetic CP533536 also attenuated uterine contractions throughout gestation. The uterotonic effects of the EP3/1 agonist sulprostone were more pronounced than the EP1 agonist ONO-D1-004, corresponding to abundant EP3 receptor expression in all samples. The contractile phenotype in mouse compared with human uteri may relate to regional differences as well as high expression of EP3 receptor transcripts. Similarities in nonpregnant and gestational tissues across species suggest that EP3 may represent a valuable translational drug target for preventing uterine hypercontractility by employing a selective antagonist. SIGNIFICANCE STATEMENT: This research validates the use of nonpregnant mice for preclinical drug discovery of uterine EP receptor targets. To determine the utility of novel drugs and delivery systems at term pregnancy and labor, pharmacological agents interacting with EP3 receptors have clear translational value.


Assuntos
Receptores de Prostaglandina E Subtipo EP2/metabolismo , Reprodução/fisiologia , Útero/metabolismo , Adulto , Animais , Cesárea/métodos , Dinoprostona/análogos & derivados , Dinoprostona/farmacologia , Feminino , Humanos , Camundongos , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Gravidez , Reprodução/efeitos dos fármacos , Contração Uterina/efeitos dos fármacos , Contração Uterina/metabolismo , Útero/efeitos dos fármacos , Adulto Jovem
8.
Top Companion Anim Med ; 38: 100370, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32115075

RESUMO

In ovariohysterectomized dogs, the uterine stump rarely causes clinical disease. However, changes could occur in this anatomic structure due to exposure to estrogen therapy. Ultrasonographic examination of the uterine stump has not been reported in dogs receiving estriol and normal dimensions for this area have not been reported for ovariohysterectomized dogs. Therefore, the aims of this study were to retrospectively evaluate records and ultrasound images from dogs receiving and not receiving (controls) estriol as well as defining a standard method to measure the uterine stump. Clinical features of dogs administered estriol were also reported. Fourteen dogs receiving estriol and 14 control dogs were included in the study. Seven dogs receiving estriol had changes associated with the external vulva, 5 were noted to be "hooded" and 3 were "prominent/swollen." Ultrasonographic transverse maximum uterine stump measurements were available for 4 dogs receiving estriol (median 0.81 cm, range 0.53-1.4). The maximum uterine height/aorta ratio was available for only 2 dogs receiving estriol (0.9 and 0.6). The median transverse maximum height of the uterine stump noted in the control group was 0.43 cm (range 0.28-0.52 cm); The maximal uterine height/aorta ratio was a median of 0.48 in the control group (range 0.32-1.1). Normal values for the uterine stump measurements can be standardized to the distal aorta for consistency. Vulvar enlargement was the most common physical examination change in our dogs receiving estriol. Routine screening, including ultrasonography is not usually indicated for dogs receiving estriol, but can be tailored to the individual patient.


Assuntos
Estriol/farmacologia , Histerectomia/veterinária , Ovariectomia/veterinária , Útero/efeitos dos fármacos , Animais , Doenças do Cão/tratamento farmacológico , Cães , Estriol/administração & dosagem , Feminino , Estudos Retrospectivos , Ultrassonografia/veterinária , Incontinência Urinária/tratamento farmacológico , Incontinência Urinária/veterinária , Útero/diagnóstico por imagem , Útero/cirurgia
9.
BMC Complement Med Ther ; 20(1): 31, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024514

RESUMO

BACKGROUND: Each year 1.5 million women experience menopause when menstrual cycles cease resulting from the loss of ovarian function and oestrogen deprivation, a hormone that helps prevent bone loss. This study investigated the effects of Physta®, a standardized herbal extract of Eurycoma longifolia Jack (PEL), on hormonal balance and parameters associated with hormonal imbalance, namely body and uterus weight and bone biochemical markers relevant in menopausal symptoms. METHODS: Forty-eight Sprague Dawley rats were randomly divided into six groups of eight rats each: (A) Sham operated; control (B) Untreated (ovariectomised (OVX) with vehicle), (C) PEL 100 (OVX + 100 mg/kg body weight (bw)), (D) PEL 300 (OVX + 300 mg/kg bw), (E) PEL 500 (OVX + 500 mg/kg bw) and (F) Positive control, testosterone undecanoate (TU) (OVX+ 10 mg/kg bw). Group A and B received daily oral administrations of the vehicle, Group C-E received daily oral administration of PEL and Group F received testosterone undecanoate intramuscularly weekly. At the end of 8 weeks, serum calcium, phosphate, bone alkaline phosphatase (BALP), osteocalcin, follicle stimulating hormone (FSH), luteinising hormone (LH), oestrogen, progesterone and testosterone were measured, then the animals were sacrificed and uterus was isolated, while weight was recorded in all experimental groups. RESULTS: Treatment of OVX rats with PEL at a dose of 500 mg/kg showed decreased serum FSH (P < 0.001, 4.25 ± 0.22 mIU/ml) and LH (NS, 4.07 ± 0.12 mIU/ml), while there was a significant increase in progesterone (P < 0.05, 2.48 ± 0.08 ng/ml) and oestrogen (P < 0.05, 11.02 ± 0.13 pg/ml) levels when compared to untreated group. PEL treatment at doses of 100 mg/kg, 300 mg/kg and 500 mg/kg showed a non-significant but increasing trend in serum calcium, phosphate, bone alkaline phosphate and testosterone levels. Ovariectomy resulted in a significant reduction (P < 0.001, 238.81 ± 5.39 mg) in uterus weight in the ovariectomised rats, which was alleviated in all PEL treated ovariectomised rats with an increasing trend of uterine weight. CONCLUSION: The results suggest that PEL could be protective and beneficial for the management of reproductive hormone and bone markers. Therefore, it could be used to address hormonal imbalances and symptoms associated with menopause.


Assuntos
Doenças Ósseas Metabólicas/metabolismo , Eurycoma/química , Hormônios Esteroides Gonadais/metabolismo , Extratos Vegetais/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Ovariectomia , Ratos , Ratos Sprague-Dawley , Útero/efeitos dos fármacos
10.
Phytomedicine ; 68: 153151, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32058234

RESUMO

BACKGROUND AND PURPOSE: Primary dysmenorrhea is the most common gynaecologic problem in menstruating women and is characterized by spasmodic uterine contraction and pain symptoms associated with inflammatory disturbances. Paeonol is an active phytochemical component that has shown anti-inflammatory and analgesic effects in several animal models. The aim of this study was to explore whether paeonol is effective against dysmenorrhea and to investigate the potential mechanism of cannabinoid receptor signalling. EXPERIMENTAL APPROACH: Dysmenorrhea was established by injecting oestradiol benzoate into female mice. The effects of paeonol on writhing time and latency, uterine pathology and inflammatory mediators were explored. Isolated uterine smooth muscle was used to evaluate the direct effect of paeonol on uterine contraction. KEY RESULTS: The oral administration of paeonol reduced dysmenorrhea pain and PGE2 and TNF-α expression in the uterine tissues of mice, and paeonol was found to be distributed in lesions of the uterus. Paeonol almost completely inhibited oxytocin-, high potassium- and Ca2+-induced contractions in isolated uteri. Antagonists of CB2R (AM630) and the MAPK pathway (U0126), but not of CB1R (AM251), reversed the inhibitory effect of paeonol on uterine contraction. Paeonol significantly blocked L-type Ca2+ channels and calcium influx in uterine smooth muscle cells via CB2R. Molecular docking results showed that paeonol fits well with the binding site of CB2R. CONCLUSIONS AND IMPLICATIONS: Paeonol partially acts through CB2R to restrain calcium influx and uterine contraction to alleviate dysmenorrhea in mice. These results suggest that paeonol has therapeutic potential for the treatment of dysmenorrhea.


Assuntos
Acetofenonas/farmacologia , Dismenorreia/tratamento farmacológico , Receptor CB2 de Canabinoide/metabolismo , Útero/efeitos dos fármacos , Acetofenonas/química , Animais , Cálcio/metabolismo , Dinoprostona/metabolismo , Dismenorreia/induzido quimicamente , Dismenorreia/metabolismo , Estradiol/análogos & derivados , Estradiol/toxicidade , Feminino , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Miócitos de Músculo Liso , Miométrio/efeitos dos fármacos , Miométrio/metabolismo , Ocitocina/farmacologia , Receptor CB2 de Canabinoide/química , Fator de Necrose Tumoral alfa/metabolismo , Contração Uterina/efeitos dos fármacos , Útero/metabolismo
11.
Int. j. morphol ; 38(1): 165-175, Feb. 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1056416

RESUMO

An alternative hyper-ovulator inducer to replace clomiphene citrate (CC) is needed as it is unsuitable for women with polycystic ovarian syndrome and is associated with low pregnancy rates. Anastrozole is an effective hyper-ovulator inducer, but has not been well researched. In order to determine the effectiveness of anastrozole as a hyper-ovulator inducer and to an extent compare it with CC in similar situations, this study ascertained the effects of these drugs on the expression of the focal adhesion proteins, paxillin and FAK, which are uterine receptivity markers in the surface luminal uterine epithelial cells of day 1 and day 6 pregnant Wistar rats. The results show that paxillin is localized in focal adhesions at the base of the uterine epithelial cells at day 1 of pregnancy whereas at day 6, paxillin disassembles from the basal focal adhesions and localizes and increases its expression apically. FAK is faintly expressed at the basal aspect of the uterine epithelial cells while moderately expressed at the cell-to-cell contact at day 1 in all groups from where it disassembles and relocates apically and becomes more intensely expressed at day 6 of pregnancy in untreated and anastrozole treated rats. Although paxillin is localized apically at day 6, its expression is significantly down-regulated with CC treatment suggesting its interference with the implantation process. These findings seem to suggest that anastrozole could favor implantation.


Para reemplazar el citrato de clomifeno (CC) es necesario un inductor de hiperovulación alternativo, ya que no es adecuado para mujeres con síndrome de ovario poliquístico y está asociado con tasas bajas de embarazo. El anastrozol es un inductor eficaz del hiper-ovulador, pero no se ha investigado adecuadamente. Con el fin de determinar la efectividad del anastrozol como inductor del hiper-ovulador y, en cierta medida, compararlo con CC en situaciones similares, este estudio determinó los efectos de estos fármacos en la expresión de las proteínas de adhesión focal, paxillin y FAK, uterinas marcadores de receptividad en la superficie luminal de células uterinas epiteliales, del día 1 y día 6 en ratas Wistar preñadas. Los resultados muestran que la paxilina se localiza en adherencias focales en la base de las células epiteliales uterinas en el día 1 del embarazo, mientras que en el día 6, la paxilina se desmonta de las adherencias focales basales y localiza y aumenta su expresión apicalmente. FAK se expresa débilmente en el aspecto basal de las células epiteliales uterinas, mientras que se expresa moderadamente en el contacto de célula a célula en el día 1 en todos los grupos, donde se separa y se reubica apicalmente y se expresa con mayor intensidad el día 6 de la preñez, en pacientes no tratados y tratados. ratas tratadas con anastrozol. Aunque la paxillina se localiza apicalmente en el día 6, su expresión está significativamente disminuida con el tratamiento con CC, lo que sugiere su interferencia con el proceso de implantación. Estos hallazgos sugieren que el anastrozol podría favorecer el proceso de implantación.


Assuntos
Animais , Feminino , Ratos , Útero/efeitos dos fármacos , Anastrozol/farmacologia , Ovulação/efeitos dos fármacos , Ratos Wistar , Adesões Focais/efeitos dos fármacos , Epitélio/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/efeitos dos fármacos , Paxilina/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Microscopia de Fluorescência
12.
Artigo em Inglês | MEDLINE | ID: mdl-32083945

RESUMO

Currently, more than 9 million American adults, including women of childbearing age, use electronic-cigarettes (e-cigs). Further, the prevalence of maternal vaping now approaching 10% is similar to that of maternal smoking. Little, however, is known about the effects of fetal exposures to nicotine-rich e-cig aerosols on lung development. In this study, we assessed whether in utero exposures to e-cig aerosols compromised lung development in mice. A third-generation e-cig device was used to expose pregnant BALB/c mice by inhalation to 36 mg/mL of nicotine cinnamon-flavored e-cig aerosols for 14-31 days. This included exposures for either 12 days before mating plus during gestation (preconception groups) or only during gestation (prenatal groups). Respective control mice were exposed to filtered air. Subgroups of offspring were euthanized at birth or at 4 wk of age. Compared with respective air-exposed controls, both preconception and prenatal exposures to e-cig aerosols significantly decreased the offspring birth weight and body length. In the preconception group, 7 inflammation-related genes were downregulated, including 4 genes common to both dams and fetuses, denoting an e-cig immunosuppressive effect. Lung morphometry assessments of preconception e-cig-exposed offspring showed a significantly increased tissue fraction at birth. This result was supported by the downregulation of 75 lung genes involved in the Wnt signaling, which is essential to lung organogenesis. Thus, our data indicate that maternal vaping impairs pregnancy outcomes, alters fetal lung structure, and dysregulates the Wnt signaling. This study provides experimental evidence for future regulations of e-cig products for pregnant women and developmentally vulnerable populations.


Assuntos
Pulmão/efeitos dos fármacos , Nicotina/efeitos adversos , Útero/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Administração por Inalação , Aerossóis/efeitos adversos , Animais , Sistemas Eletrônicos de Liberação de Nicotina , Feminino , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Organogênese/efeitos dos fármacos , Gravidez , Resultado da Gravidez
13.
Acta Obstet Gynecol Scand ; 99(5): 571-581, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31889294

RESUMO

INTRODUCTION: The levonorgestrel intrauterine system (LNG-IUS) is a long-acting hormone-releasing uterine device that has many non-contraceptive benefits. The study aims to assess the safety and efficacy of LNG-IUS in the management of adenomyosis. MATERIAL AND METHODS: We searched the following bibliographic databases: MEDLINE via PubMed, SCOPUS, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE and Google Scholar for the relevant studies which used LNG-IUS in management of patients with clinically or ultrasonographic diagnosed adenomyosis.The main outcome measures are pain score at the end of follow-up, bleeding, symptomatic relief, uterine volume (mL), endometrial thickness (mm) and/or hemoglobin level. RESULTS: Ten prospective studies (patients n = 551) were included. The overall effect estimates showed that the LNG-IUS led to significant reductions in pain score after 12 months (standardized mean difference [SMD[ -3.87, 95% confidence interval [CI] -5.51 to -2.23, P < .001), 24 months (SMD -5.56, 95% CI -9.80 to -1.32, P = .01) and 36 months of insertion (SMD -3.81, 95% CI -4.27 to -3.36, P < .001). Similarly, the Pictorial Blood Assessment Chart (PBAC) showed significant reduction up to 36 months after LNG-IUS insertion (SMD -2.32, 95% CI -2.91 to -1.73, P < .001). The LNG-IUS led to significant reductions in the uterine volume 12 months (SMD -.60, 95% CI -0.88 to -.31, P < .001) and 36 months after insertion (SMD -0.42, 95% CI -0.69 to -0.14, P = .003). CONCLUSIONS: LNG-IUS is a promising and effective option for the management of adenomyosis. Its use effectively reduced the severity of symptoms, uterine volume and endometrial thickness, and improved laboratory outcomes.


Assuntos
Adenomiose/tratamento farmacológico , Dispositivos Intrauterinos Medicados , Levanogestrel/uso terapêutico , Congêneres da Progesterona/uso terapêutico , Feminino , Humanos , Estudos Prospectivos , Resultado do Tratamento , Útero/efeitos dos fármacos
14.
FASEB J ; 34(1): 446-457, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914682

RESUMO

Mechanical damage or infection to the endometrium can lead to the formation of adhesions in the uterine cavity, which may result in reduced reproductive outcome and/or pregnancy complications. The prognosis of this disease is poor due to few effective treatments and the complex environment of endometrium. Heparin-Poloxamer Hydrogel (HP hydrogel) is a nontoxic and biodegradable biomaterial, which has been commonly used as a sustained-release delivery system. In this study, we applied a mini-endometrial curette to scrape the endometrium of rats to mimic the process of curettage in patients. After the establishment of IUA model in rats, we injected the thermo-sensitive hydrogel(E2-HP hydrogel) into the injured uterine cavity and evaluated the therapeutic effect of E2-HP hydrogel on the recovery of IUA. Our results showed that E2-HP hydrogel can significantly facilitate the regeneration of injured endometrium along with inhibiting the cell apoptosis in IUA model. Furthermore, we revealed that E2-HP hydrogel on the recovery of IUA was closely associated with the upregulation of kisspeptin through activating the ERK1/2 and MAPKs p38 pathways. In conclusion, E2-HP hydrogel can effectively transfer E2 into the injured endometrium and it can be considered as a promising therapeutic method for the women with intrauterine adhesions.


Assuntos
Endométrio/citologia , Estradiol/farmacologia , Heparina/química , Hidrogéis/farmacologia , Poloxâmero/química , Regeneração , Aderências Teciduais/tratamento farmacológico , Útero/citologia , Animais , Endométrio/efeitos dos fármacos , Endométrio/lesões , Estradiol/química , Feminino , Hidrogéis/química , Gravidez , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Útero/efeitos dos fármacos , Útero/lesões
15.
J Morphol ; 281(3): 302-315, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31904879

RESUMO

Artibeus lituratus is a frugivorous bat that directly assists in the restoration of degraded habitats through the effective dispersion of seeds and fruits. Given its great importance, this work aimed to evaluate the uterine hormonal control of A. lituratus during its different reproductive phases. The uteri of 30 sexually mature adult females, five specimens for each of the six sample groups (NON, nonreproductive; P1, initial pregnancy; P2, intermediate pregnancy; P3, advanced pregnancy; LAC, lactating; P + LAC, pregnant-lactating), were submitted to analyses of serum estradiol and progesterone concentrations, in addition to immunohistochemical analyses. Both estradiol and progesterone, gradually increased during pregnancy, with a marked significant increase in P3 females. Both returned to low levels in LAC-females; however, estradiol levels decreased further in P + LAC-females, while progesterone increased in the same group. In general, signs indicative of aromatase expression were observed in the endometrium of all analyzed groups and in the placenta of bats in the gestation groups. Similarly, ERα and PR were expressed in the myometrium, endometrium and placenta at varying levels of intensity. The results indicate that the uterine microenvironment of A. lituratus is directly regulated by serum concentrations of estradiol and progesterone, and fluctuations in these concentrations control morphological and physiological changes of this organ during different phases of the reproductive cycle. RESEARCH HIGHLIGHTS: Increases in serum concentrations of estradiol and progesterone coordinate the gestational period of A. lituratus. Estradiol activates ERα, stimulating cell proliferation in the uterus, in addition to activating the expression of PR, which trigger the quiescence of the myometrium and stimulation of the secretion and differentiation of the endometrium. Results showed several similarities to humans, indicating the use of A. lituratus as an animal model in reproductive studies.


Assuntos
Quirópteros/fisiologia , Hormônios/farmacologia , Reprodução/fisiologia , Útero/fisiologia , Animais , Aromatase/metabolismo , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Feminino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Receptores de Progesterona/metabolismo , Útero/anatomia & histologia , Útero/citologia , Útero/efeitos dos fármacos
16.
Am J Pathol ; 190(2): 295-305, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31837289

RESUMO

Preterm birth (PTB) affects nearly 15 million infants each year. Of these PTBs, >25% are a result of inflammation or infection. Animal models have improved our understanding of the mechanisms leading to PTB. Prior work has described induction of intrauterine inflammation in mice with a single injection of lipopolysaccharide (LPS). Herein, we have improved the reproducibility and potency of LPS in the model using two injections distal to the cervix. An in vivo imaging system revealed more uniform distribution of Evans Blue Dye using a double distal injection (DDI) approach compared with a single proximal injection (SPI). Endotoxin concentrations in vaginal lavage fluid from SPI dams were significantly higher than from DDI dams. At equivalent LPS doses, DDI consistently induced more PTB than SPI, and DDI showed a linear dose-response, whereas SPI did not. Gene expression in myometrial tissue revealed increased levels of inflammatory markers in dams that received LPS DDI compared with LPS SPI. The SPI group showed more significant overexpression in cervical remodeling genes, likely due to the leakage of LPS from the uterine horns through the cervix. The more reliable PTB induction and uniform uterine exposure provided by this new model will be useful for further studying fetal outcomes and potential therapeutics for the prevention of inflammation-induced PTB.


Assuntos
Modelos Animais de Doenças , Inflamação/complicações , Lipopolissacarídeos/toxicidade , Miométrio/patologia , Nascimento Prematuro/etiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Animais , Feminino , Inflamação/induzido quimicamente , Inflamação/patologia , Camundongos , Miométrio/efeitos dos fármacos , Miométrio/imunologia , Gravidez , Nascimento Prematuro/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Útero/efeitos dos fármacos
17.
Ecotoxicol Environ Saf ; 190: 110069, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841894

RESUMO

Carbon disulfide (CS2) is regarded as a common occupational poison that is widely used in the textile industry in China. Our previous research suggests that CS2 can induce significant implantation disorders in pregnant mice; however, the specific mechanism remains unclear. Uterine conception in mice must undergo decidualization, which is the prerequisite for propitious blastocyst implantation into the endometrium. Therefore, in this study, we established models of pregnant mice to explore the toxic effects of CS2 on decidualization to elucidate the basic mechanism of implantation disorder after CS2 exposure. The uterine tissues were immediately collected according to the predetermined endpoints to measure the expression levels of IGFBP1 and PRL (markers of decidualization differentiation), IL-11 (representing the secretory function of decidual cells), AKT and pAKT by western blotting, RT-PCR, immunohistochemical staining, H&E staining and ELISA. N-carbamoyl glutamic acid (NCG) acted as an agonist of AKT to verify the upstream regulatory mechanism of decidualization disorder by CS2. The results showed that the normal reaction of decidual transformation was obviously disrupted by CS2 upon 3.5 dpc and 4.5 dpc exposure. The blastocyst did not adhere to the epithelium after 3.5 dpc-exposure and did not invade the endometrium after 4.5 dpc-exposure, resulting in its suspension in the uterine cavity, stagnation and eventual loss. The proteins expression levels were decreased by 95.2% for IGFBP1 and 76.2% for PRL at the 4.5 dpc endpoint after 3.5 dpc CS2 exposure compared with the control. Simultaneously, the mRNA and protein expression levels of IL-11 in uterine tissues were significantly reduced by CS2, and consistent decreasing trends over time were observed for IGFBP1 and PRL, compared with the control. Additionally, the ratio of pAKT/AKT protein expression was decreased by 72.2% and 94.8% at 12 h and 18 h after 3.5 dpc exposure and by 53.3% and 74.3% at 6 h and 12 h after 4.5 dpc exposure, respectively, compared with the corresponding controls. Furthermore, NCG could recover the IGFBP1 and PRL protein expression, which was increased by 27.5% and 52.3% at 4.5 dpc and 6.5 dpc, respectively, after 3.5 dpc exposure for IGFBP1 and by 30.3% at 6.5 dpc after 4.5 dpc exposure for PRL, compared with CS2 exposure alone. Collectively, this study suggested that the decidualization disorder caused by CS2 at the window of implantation in pregnant mice, which is triggered by pAKT, contributed to the implantation disorder and eventually led to embryo loss. It is worth noting that our study may provide a new perspective and reference for exploring the toxic mechanism of implantation disorder and even infertility in harmful circumstances.


Assuntos
Dissulfeto de Carbono/toxicidade , Implantação do Embrião/efeitos dos fármacos , Útero/efeitos dos fármacos , Animais , Diferenciação Celular , Endométrio/fisiologia , Feminino , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Interleucina-11/genética , Interleucina-11/metabolismo , Camundongos , Gravidez , Prolactina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Útero/metabolismo
18.
Toxicol Lett ; 318: 99-103, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669098

RESUMO

Fluorination preventing metabolic hydroxylation of 17ß-estradiol (E2) was applied to investigate the mechanisms underlying estrogen-induced carcinogenesis. Either 2-fluoro-17ß-estradiol (2-FE2) or 4-fluoro-17ß-estradiol (4-FE2) was administered subcutaneously for 52 weeks to August Copenhagen Irish (ACI) rats, the preferred animal model for human breast cancer. 4-FE2 induced frequent mammary tumors whereas 2-FE2 did not. The cumulative incidence of mammary tumors in rats treated with 4-FE2 was comparable to that observed with E2. The carcinogenic results were supported by histological examination of mammary glands of fluorinated estrogen-treated ACI rats. To evaluate the estrogenic potential of the fluorinated estrogens, 2-FE2 or 4-FE2 was administrated subcutaneously to ovariectomized rats. Both 4-FE2 and 2-FE2 showed high uterotrophic potency. Our results indicate that estrogenic potential may not be the sole factor driving mammary tumorigenesis. Since fluorination inhibits metabolic hydroxylation of E2 at the substituted position, the carcinogenic effect may occur through the metabolic activation of 2-hydroxylated E2, in combination with the compound's estrogenic potency.


Assuntos
Neoplasias da Mama/induzido quimicamente , Transformação Celular Neoplásica/induzido quimicamente , Estradiol/análogos & derivados , Animais , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/patologia , Estradiol/toxicidade , Feminino , Tamanho do Órgão/efeitos dos fármacos , Ratos Endogâmicos ACI , Medição de Risco , Útero/efeitos dos fármacos , Útero/patologia
19.
Ecotoxicol Environ Saf ; 188: 109898, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31711775

RESUMO

Gamma-aminobutyric acid (GABA) plays a critical role in regulation of gonadotropin-releasing hormone (GnRH) through GABAA receptor (GABAAR). Nitric oxide (NO) production has correlation with GABA and regulates GnRH secretion. This study was performed to examine the mechanisms by which manganese (Mn) accelerate puberty onset involves GABAAR/NO pathway in the preoptic area-anterior hypothalamus (POA-AH) in immature female rats. First, female rats received daily dose of MnCl2 0 (saline), 2.5, 5 and 10 mg/kg b.w by oral gavage during postnatal day (PND) 21-32. Animals administered with 10 mg/kg MnCl2 exhibited earlier puberty onset age and advanced ovary and uterus development than these in saline-treatment group. Furthermore, we found that decrease of GABAAR result in elevated production of nitric oxide synthase1 (NOS1), NO and GnRH in the POA-AH. Second, we recorded the neuronal spikes alternation after perfusion with GABAAR inhibitor bicuculline (BIC), GABAAR agonist isoguvacine (isog), and MnCl2 from the POA-AH in acute brain slices of PND21 rats. Spontaneous firing revealed a powerful GABAAR-mediated action on immature POA-AH and confirm that MnCl2 has a significant effect on GABAAR. Third, we revealed that decrease in NOS1 and NO production by treatment with isog-alone or isog+MnCl2 contribute to the decrease of GnRH in the POA-AH and a delayed puberty onset age compared to treatment with MnCl2-alone. Together, these results suggested that excessive exposure to MnCl2 stimulates NO production through decreased GABAAR in the POA-AH to advance puberty onset in immature female rats.


Assuntos
Envelhecimento/efeitos dos fármacos , Cloretos/toxicidade , Disruptores Endócrinos/toxicidade , Óxido Nítrico/metabolismo , Área Pré-Óptica/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Maturidade Sexual/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Compostos de Manganês , Neurônios/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Área Pré-Óptica/crescimento & desenvolvimento , Área Pré-Óptica/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Útero/diagnóstico por imagem , Útero/efeitos dos fármacos , Desmame
20.
Theriogenology ; 142: 338-347, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31711709

RESUMO

The objective of this study was to determine the effects of prepartum negative dietary cation-anion difference diet (DCAD) fed at two dietary Ca inclusion rates on postpartum uterine health and ovulation dynamics of multiparous Holstein cows (n = 76). Treatments began at 28 days before expected calving until parturition and were: CON: DCAD = +6 mEq/100g of DM with low dietary Ca (46.2 ± 15.2 g Ca/d; 0.4% DM; n = 26); ND: DCAD = -24 mEq/100g of DM with low dietary Ca (44.1 ±â€¯16.1 Ca/d; 0.4% DM; n = 24); NDCA: DCAD = -24 mEq/100g of DM with high dietary Ca (226.6 ±â€¯96.0 g Ca/d; 2.0% DM; n = 26). Vaginal discharge was evaluated through the fresh period via Metricheck (MC) for presence of purulent material. Polymorphonuclear (PMN) cell concentration in the uterus was evaluated at 15 and 30 days relative to calving (DRC). Endometrial tissue was harvested at 30 DRC for glandular morphology, presence of tight-junctions and adheren-junctions proteins, as well as assessment of superoxide dismutase (SOD) and glutathione peroxidase (GPX) activity. Blood plasma and serum samples were harvested in the prepartum and postpartum phase and were assessed for concentrations of lipopolysaccharide binding protein (LBP), serum amyloid A (SAA), and haptoglobin (HP). Ovarian dynamics were assessed through the fresh period until first timed artificial insemination (TAI). Cows fed CON had a lower MC score (P = 0.06) than the average of cows fed ND and cows fed NDCA. Cows fed ND had a higher MC score than cows fed NDCA. Cows fed NDCA had greater uterine gland epithelial height (P = 0.02) than cows fed ND. Cows fed NDCA also had a greater number of epithelial cells per gland (P = 0.05) than cows fed ND. Cows fed NDCA had greater intensity of occludin expression (P = 0.15) than cows fed ND. Cows fed NDCA had increased activity of SOD (P = 0.05) and decreased activity of GPX (P < 0.001) than cows fed ND. Cows fed ND had higher plasma HP concentrations than cows fed NDCA in the prepartum (P = 0.01) and post-partum (P = 0.03) periods. Cows fed ND and NDCA had lower (P = 0.01) postpartum plasma HP concentration than cows fed CON. In conclusion, cows fed NDCA had an improved uterine environment most likely due to alleviation of oxidative stress, an enhanced immune response to parturition and uterine discharge comparable to cows fed CON.


Assuntos
Ácidos/administração & dosagem , Cálcio na Dieta/administração & dosagem , Endometrite/prevenção & controle , Fertilidade/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição Materna , Transtornos Puerperais/prevenção & controle , Útero/efeitos dos fármacos , Ácidos/farmacologia , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Cálcio na Dieta/farmacologia , Bovinos , Doenças dos Bovinos/prevenção & controle , Dieta/veterinária , Endometrite/veterinária , Feminino , Fertilidade/fisiologia , Lactação/efeitos dos fármacos , Lactação/fisiologia , Fenômenos Fisiológicos da Nutrição Materna/efeitos dos fármacos , Leite , Período Pós-Parto/efeitos dos fármacos , Gravidez , Transtornos Puerperais/veterinária , Útero/fisiologia
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