RESUMEN
(-)-Carvone, a ketone monoterpene, is the main component of essential oils from several medicinal plants and has been reported to have anti-arthriric, anticonvulsive, antidiabetic, anti-inflammatory, anticancer, and immunomodulatory effects. Therefore, this study aimed to investigate the spasmolytic activity of (-)-carvone in rodent models. The isolated virgin rat uterus was mounted in an organ bath apparatus, and the relaxing effect of ( -)-carvone and its mechanism of action were evaluated in tonic contractions induced by carbachol, KCl, PGF2α, or oxytocin. The animal model of primary dysmenorrhea was replicated with the injection of estradiol benzoate in female mice for three consecutive days, followed by intraperitoneal administration of oxytocin. Non-clinical acute toxicity evaluation was also performed. (-)-Carvone potency and effectiveness were larger in carbachol (pEC50 = 5.41 ± 0.14 and Emax = 92.63 ± 1.90% at 10-3 M) or oxytocin (pEC50 = 4.29 ± 0.17 and Emax = 86.69 ± 1.56% at 10-3 M) contractions. The effect of ( -)-carvone was altered in the presence of 4-aminopyridine, glibenclamide, L-NAME, or methylene blue. Mice pre-treated with (-)-carvone at a dose of 100 mg/kg showed a significant reduction in the number of writhing after oxytocin administration. No toxicity was observed after oral administration of 1 g/kg ( -)-carvone. Taken together, we showed that (-)-carvone reduced writhing by a spasmolytic effect, probably through the participation of KV and KATP channels and the nitric oxide pathway.
Asunto(s)
Monoterpenos Ciclohexánicos , Monoterpenos , Oxitocina , Útero , Animales , Oxitocina/farmacología , Femenino , Monoterpenos Ciclohexánicos/farmacología , Ratones , Útero/efectos de los fármacos , Monoterpenos/farmacología , Contracción Uterina/efectos de los fármacos , Ratas , Ratas Wistar , Parasimpatolíticos/farmacología , Relajación Muscular/efectos de los fármacos , Carbacol/farmacologíaRESUMEN
Pyriproxyfen (PPF) is an insecticide used in agriculture, which is approved for use in drinking water tanks for human consumption. However, some studies indicate that it may act as an endocrine disruptor and affect nontarget organisms. This study aimed to evaluate the effects of PPF on reproduction and general health status in female mice exposed from pre-puberty to adulthood. In the first experiment, females were treated by gavage from postnatal day (PND) 23 to (PND) 75 and were distributed into three experimental groups: control (vehicle), PPF 0.1 mg/kg, and PPF 1 mg/kg. Female mice were assessed for the age of puberty onset, body mass, water and food consumption, and the estrous cycle. On PDN 75, a subgroup was euthanized, when vital and reproductive organs were collected and weighed. The thyroid, ovary, and uterus were evaluated for histomorphometry. The other subgroup was assessed in relation to reproductive performance and fetal parameters. In a second experiment, the uterotrophic assay was performed with juvenile females (PND 18) using doses of 0.01, 0.1, or 1 mg/kg of PPF. PPF treatment reduced thyroid mass and increased liver mass. Furthermore, there was an increase in ovarian interstitial tissue and, in the uterus, a decrease in the thickness of the endometrial stroma with reduced content of collagen fibers. There was also a reduction of 30% in pregnancy rate in the treated groups and an increase in the frequency of fetal death. This study suggests that, based on this experimental model, the insecticide may pose a reproductive risk for females chronically exposed to the substance from the pre-pubertal period until adulthood. These results raise concerns about prolonged exposure of women to the same compound.
Asunto(s)
Insecticidas , Piridinas , Reproducción , Maduración Sexual , Femenino , Animales , Ratones , Piridinas/toxicidad , Embarazo , Maduración Sexual/efectos de los fármacos , Insecticidas/toxicidad , Reproducción/efectos de los fármacos , Muerte Fetal , Ovario/efectos de los fármacos , Ovario/crecimiento & desarrollo , Útero/efectos de los fármacos , Útero/crecimiento & desarrollo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Disruptores Endocrinos/toxicidad , Glándula Tiroides/efectos de los fármacosRESUMEN
OBJECTIVES: Despite regular gender-affirming hormone therapy (GAHT), the presence of uterine bleeding can occur occasionally and cause profound discomfort. This study aimed to evaluate the histologic features and immunohistochemical expression of estrogen (ER), progesterone (PR), and androgen receptors (AR) in the endometrium and myometrium of transgender men receiving testosterone therapy and relate them to clinical and hormonal characteristics. DESIGN: Retrospective cross-sectional study. METHODS: Thirty-four transgender men undergoing gender-affirming surgery were included. Clinical, sociodemographic, and laboratory data as well as anatomopathological and immunohistochemical findings were evaluated. RESULTS: The participants' mean age was 42.35 (SD, 10.00) years, and body mass index was 28.16 (SD, 5.52) kg/m2. The mean GAHT duration before surgery was 5.36 (SD, 3.24) years. The mean testosterone levels were 814.98 (SD, 407.13) ng/dL, and estradiol levels were 55.22 (SD, 25.27) pg/mL. The endometrium was atrophic in 61.8%, proliferative in 17.6%, and secretory in 20.6%. Immunohistochemical receptor analysis revealed that endometrial epithelial cells expressed ER (90%) and PR (80%), with a lower expression of AR (30%). In stromal tissue, the median ER, PR, and AR expression was lower than that in the epithelium (60%, 70%, and 25%, respectively). The myometrium showed high expression of PR (90%) and ER (70%), with the highest expression of AR (65%) being localized to this region. CONCLUSIONS: In the present study, GAHT induced an atrophic condition of the endometrium in two-thirds of the transgender men, with a limited AR expression in the endometrial region. The present results suggest that testosterone-based GAHT for a mean of 5 years is safe in transgender men achieving amenorrhea.
Asunto(s)
Endometrio , Receptores Androgénicos , Testosterona , Personas Transgénero , Humanos , Estudios Retrospectivos , Adulto , Estudios Transversales , Masculino , Femenino , Persona de Mediana Edad , Endometrio/efectos de los fármacos , Endometrio/metabolismo , Endometrio/patología , Receptores Androgénicos/metabolismo , Receptores de Progesterona/metabolismo , Útero/metabolismo , Útero/patología , Útero/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Procedimientos de Reasignación de Sexo/efectos adversos , Miometrio/metabolismo , Miometrio/patología , Miometrio/efectos de los fármacosRESUMEN
This study aimed to assess the impact of protein supplementation and its interaction with calf sex (CS) on the performance, metabolism and physiology of pregnant beef cows. Fifty-two multiparous Zebu beef cows carrying female (n = 22) and male (n = 30) fetuses were used. Cows were individually housed from day 100 to 200 of gestation and randomly assigned to restricted (RES, n = 26) or supplemented (SUP, n = 26) groups. The RES cows were ad libitum fed a basal diet (corn silage + sugarcane bagasse + mineral mixture), achieving 5.5% crude protein (CP), while SUP cows received the same basal diet plus a protein supplement (40% CP, at 3.5 g/kg of body weight). All cows were fed the same diet during late gestation. Differences were declared at p < 0.05. No significant interaction between maternal nutrition and calf sex was found for maternal outcomes (p ≥ 0.34). The SUP treatment increased the total dry matter (DM) intake (p ≤ 0.01) by 32% and 19% at mid- and late-gestation respectively. The total tract digestibility of all diet components was improved by SUP treatment at day 200 of gestation (p ≤ 0.02), as well as the ruminal microbial CP production (p ≤ 0.01). The SUP treatment increased (p ≤ 0.03) the cows' body score condition, ribeye area, the average daily gain (ADG) of pregnant components (PREG; i.e., weight accretion of cows caused by pregnancy) and the ADG of maternal tissues (i.e., weight accretion discounting the gain related to gestation) in the mid-gestation. The SUP cows exhibited a lower maternal ADG (p < 0.01) compared to RES cows in late pregnancy. There was a 24% additional gain (p < 0.01) in the PREG components for SUP cows during late gestation, which in turn improved the calf birthweight (p = 0.05). The uterine arterial resistance and pulsatility indexes (p ≤ 0.01) at mid-gestation were greater for RES cows. In conclusion, protein supplementation during mid-gestation is an effective practice for improving maternal performance, growth of the gravid uterus and the offspring's birth weight.
Asunto(s)
Alimentación Animal , Fenómenos Fisiológicos Nutricionales de los Animales , Dieta , Proteínas en la Dieta , Suplementos Dietéticos , Útero , Animales , Bovinos/fisiología , Femenino , Alimentación Animal/análisis , Embarazo , Dieta/veterinaria , Proteínas en la Dieta/administración & dosificación , Proteínas en la Dieta/farmacología , Útero/efectos de los fármacos , Masculino , Digestión/efectos de los fármacos , Digestión/fisiología , Fenómenos Fisiologicos Nutricionales Maternos , Ingestión de Alimentos/efectos de los fármacosRESUMEN
This study evaluated whether the treatment of pseudopregnancy in bitches with vitamin B6 modulates uterine expression of receptors for progesterone (PR), oestrogen (ERα), androgen (AR), thyroid hormone (TRα) and the kisspeptin/Kiss1r system. Eighteen pseudopregnant bitches were treated for 20 days in groups receiving placebo (n = 6); cabergoline (5 µg/kg/day; n = 6); or vitamin B6 (50 mg/kg/day; n = 6). Blood was collected on the 1st day of drug administration and 120 h later to measure serum prolactin (PRL). After treatment, they were ovariohysterectomized and uterine fragments were collected for histomorphometry and immunohistochemical evaluation of PR, ERα, AR, TRα, Kiss1 and Kiss1r. After 120 h of cabergoline or vitamin B6 treatment, PRL levels were reduced in the bitches, confirming the antiprolactinemic effect of these drugs. Furthermore, regardless of treatment, the animals exhibited uterine histomorphometry consistent with dioestrus. The PR showed strong immunostaining in all regions and an increase in scores was observed for this receptor in animals treated with vitamin B6 in deep glands. In contrast, ERα and Kiss1R receptors showed weak to no immunostaining in all uterine regions and no changes between groups. Regarding AR, most animals treated with vitamin B6 showed increased trends in the deep gland and myometrium marking scores. In contrast, in both vitamin B6 and cabergoline treatments, a reduction in TRα marking scores was observed compared to the control group. In addition, on the endometrial surface, a reduction was observed in the marked area of Kiss1 after administration of cabergoline when compared to the pseudopregnant control group. These findings shed valuable insight into the use of vitamin B6 as a drug with actions similar to cabergoline in reducing PRL and uterine modulation in bitches.
Asunto(s)
Cabergolina , Kisspeptinas , Prolactina , Seudoembarazo , Útero , Vitamina B 6 , Animales , Perros , Femenino , Cabergolina/farmacología , Ergolinas/farmacología , Kisspeptinas/farmacología , Kisspeptinas/metabolismo , Prolactina/metabolismo , Seudoembarazo/veterinaria , Seudoembarazo/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Progesterona/metabolismo , Útero/efectos de los fármacos , Útero/metabolismo , Vitamina B 6/metabolismo , Vitamina B 6/farmacologíaRESUMEN
SUMMARY: The study explores the relationship between chronic exposure to fine particulate matter (PM2.5), sourced from wood smoke, and the histological structure and endocrine function of the uterus in nulliparous adult rats. It assesses potential structural changes in the uterus that could impact reproductive health, viewing PM2.5 exposure as a possible risk factor. A controlled experiment was conducted in a city known for high air pollution levels, exposing rats to filtered and unfiltered air conditions, thus mimicking human PM2.5 exposure. Histological findings indicated a significant increase in collagen density and uterine wall thickness in PM2.5 exposed subjects, suggesting a reproductive function risk. However, no significant differences were observed in progesterone and estradiol hormone levels, pointing to the complex relationship between PM2.5 exposure and its endocrine impact, and emphasizing the need for further studies for a deeper understanding. This work highlights the importance of thoroughly investigating the long-term effects of PM2.5 pollution on reproductive health, underlining the significance of considering environmental exposure as a critical factor in reproductive health research.
El estudio explora la relación entre la exposición crónica a partículas finas (PM2,5), procedentes del humo de leña, y la estructura histológica y la función endocrina del útero en ratas adultas nulíparas. Evalúa posibles cambios estructurales en el útero que podrían afectar la salud reproductiva, considerando la exposición a PM2,5 como un posible factor de riesgo. Se llevó a cabo un experimento controlado en una ciudad conocida por sus altos niveles de contaminación del aire, exponiendo ratas a condiciones de aire filtrado y sin filtrar, imitando así la exposición humana a PM2,5. Los hallazgos histológicos indicaron un aumento significativo en la densidad del colágeno y el grosor de la pared uterina en sujetos expuestos a PM2,5, lo que sugiere un riesgo para la función reproductiva. Sin embargo, no se observaron diferencias significativas en los niveles de las hormonas progesterona y estradiol, lo que apunta a la compleja relación entre la exposición a PM2,5 y su impacto endocrino, y enfatiza la necesidad de realizar más estudios para una comprensión más profunda. Este trabajo destaca la importancia de investigar a fondo los efectos a largo plazo de la contaminación por PM2,5 en la salud reproductiva, subrayando la importancia de considerar la exposición ambiental como un factor crítico en la investigación de la salud reproductiva.
Asunto(s)
Animales , Femenino , Ratas , Humo/efectos adversos , Útero/efectos de los fármacos , Madera , Ratas Sprague-Dawley , Contaminantes Atmosféricos/toxicidad , Contaminación del Aire , Material Particulado/toxicidad , Genitales Femeninos/efectos de los fármacosRESUMEN
We aimed to evaluate the effects of administering estradiol (E-17ß) at the moment of timed-AI (TAI) on uterine gene expression, estrous expression rate (EER), and pregnancy rate (P/TAI) in Nelore cows with a small dominant follicle (DF) or not showing estrus at TAI. In Experiments 1 and 2 (Exp1, Exp2) cows were submitted to a P4/E-17ß-based protocol (day 0) for synchronization of ovulation. On day 7, devices were removed, cows received 1 mg E-17ß cypionate and 12.5 mg dinoprost. On day 9, cows with DF < 11.5 mm in diameter were split into different groups. In Exp1 (n = 16/group): Control (no treatment), E-2 (2 mg E-17ß) and E-4 (4 mg E-17ß). In Exp2: Control (n = 12); E-2 (n = 14); GnRH (0.1 mg gonadorelin acetate, n = 13); and E-2+GnRH (association of GnRH and E-17ß, n = 13). Between days 9 and 11, endometrial thickness (ET), time of ovulation detection, and EER were recorded. In Exp1, a uterine cytological sample was collected 4 h after treatment to evaluate the transcript expression of receptors for E-17ß (ESR1 and ESR2), oxytocin (OXTR), and P4 (PGR). In Experiment 3 (Exp3), 3829 suckled cows were submitted to a P4/E-17ß-based protocol for TAI. On day 9, devices were removed and cows received 1 mg E-17ß cypionate and 0.4 mg sodium cloprostenol. On day 11, TAI was performed and cows that did not demonstrate estrus received 0.1 mg gonadorelin acetate, and were allocated into two groups: GnRH (n = 368) and E-2+GnRH (2 mg E-17ß; n = 363). In Exp1, plasma E-17ß concentrations increased at 4 h after treatment in a dose-dependent manner but reduced at 12 h. The E-17ß-treated cows had greater transcript abundance for OXTR and lesser for ESR1 and ESR2, and the ET was reduced 12 h after treatment (P < 0.05). No significant difference (P > 0.1) was observed between the E-17ß doses in estrus or ovulation rate. In Exp2, the interval from treatment to ovulation was longer (P < 0.05) in the E-17ß group. GnRH-treated cows showed higher ovulation rates (89 vs. 35 %) compared to cows not treated with GnRH, as E-17ß-treated cows (P < 0.01) had a lower ovulation rate compared to those not receiving E-17ß (44 vs. 78 %). In Exp3, P/TAI was 55 % for cows in estrus. For those not showing estrus, no difference (P > 0.1) in P/TAI was observed between GnRH (34 %) and E-2+GnRH (31 %) groups. Cows with a DF ≥ 11 mm (n = 192) had a greater (P < 0.05) P/TAI (49 %) than those with DF < 11 mm (n = 377; 29 %). In conclusion, E-17ß administration in the moment of TAI modulates the mRNA expression of uterine receptors in cows with a small DF but does not impact the P/TAI compared with GnRH treatment in suckled Nelore not showing estrus previous to TAI.
Asunto(s)
Estradiol , Inseminación Artificial , Folículo Ovárico , Animales , Bovinos/fisiología , Femenino , Estradiol/farmacología , Estradiol/administración & dosificación , Estradiol/análogos & derivados , Embarazo , Inseminación Artificial/veterinaria , Folículo Ovárico/efectos de los fármacos , Sincronización del Estro/métodos , Sincronización del Estro/efectos de los fármacos , Estro/efectos de los fármacos , Útero/efectos de los fármacos , Índice de EmbarazoRESUMEN
PURPOSE: Osteoporosis is a bone disease which commonly occurred in postmenopausal women. Almost 10 percent of world population and approximately 30% of women (postmenopausal) suffer from this disease. Alternative medicine has great success in the treatment of osteoporosis disease. Bryodulcosigenin, a potent phytoconstituent, already displayed the anti-inflammatory and antioxidant effect. In this study, we made effort to analyze the antiosteoporosis effect of bryodulcosigenin against ovariectomy (OVX) induced osteoporosis in rats. METHODS: Swiss albino Wistar rats were grouped into fIve groups and given an oral dose of bryodulcosigenin (10, 20 and 30 mg/kg) for eight weeks. Body weight, uterus, bone mineral density, cytokines, hormones parameters, transforming growth factor (TGF)-ß, insulin-like growth factor (IGF), osteoprotegerin (OPG), receptor activator of nuclear factor kappa-Β ligand (RANKL), and its ratio were estimated. RESULTS: Bryodulcosigenin significantly (p < 0.001) suppressed the body weight and enhanced the uterine weight and significantly (p < 0.001) increased the bone mineral density in whole femur, caput femoris, distal femur and proximal femur. Bryodulcosigenin significantly (P < 0.001) altered the level of biochemical parameters at dose dependent manner, significantly (P < 0.001) improved the level of estrogen and suppressed the level of follicle stimulating hormone and luteinizing hormone. Bryodulcosigenin significantly (P < 0.001) improved the level of OPG and suppressed the level of RANKL. CONCLUSIONS: Bryodulcosigenin reduced the cytokines level and suppressed the TGF-ß and IGF. We concluded that bryodulcosigenin is an antiosteoporosis medication based on the findings.
Asunto(s)
Densidad Ósea , Osteoporosis , Ovariectomía , Ratas Wistar , Animales , Femenino , Densidad Ósea/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & control , Osteoporosis/etiología , Ratas , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Útero/efectos de los fármacos , Citocinas/sangre , Citocinas/efectos de los fármacos , Fémur/efectos de los fármacos , Resultado del TratamientoRESUMEN
Exposure to glyphosate-based herbicides (GBH) and consumption of cafeteria (CAF) diet, which are widespread in Western society, seem to be associated with endometrial hyperplasia (EH). Here, we aimed to evaluate the effects of a subchronic low dose of GBH added to the CAF diet on the rat uterus. Female Wistar rats were fed from postnatal day (PND)21 until PND240 with chow (control) or CAF diet. Since PND140, rats also received GBH (2 mg of glyphosate/kg/day) or water through food, yielding four experimental groups: control, CAF, GBH, and CAF+GBH. On PND240, CAF and CAF+GBH animals showed an increased adiposity index. With respect to the control group, no changes in the serum levels of 17ß-estradiol and progesterone were found. However, progesterone levels were higher in the CAF+GBH group than in the CAF and GBH groups. In the uterus, both studied factors alone and in combination induced morphological and molecular changes associated with EH. Furthermore, the addition of GBH provoked an increased thickness of subepithelial stroma in rats fed with the CAF diet. As a consequence of GBH exposure, CAF+GBH rats exhibited an increased density of abnormal gland area, considered preneoplastic lesions, as well as a reduced PTEN and p27 expression, both tumor suppressor molecules that inhibit cell proliferation, with respect to control rats. These results indicate that the addition of GBH exacerbates the CAF effects on uterine lesions and that the PTEN/p27 signaling pathway seems to be involved. Further studies focusing on the interaction between unhealthy diets and environmental chemicals should be encouraged to better understand uterine pathologies.
Asunto(s)
Glicina , Glifosato , Herbicidas , Ratas Wistar , Útero , Animales , Femenino , Útero/efectos de los fármacos , Útero/patología , Útero/metabolismo , Herbicidas/toxicidad , Glicina/análogos & derivados , Ratas , Hiperplasia Endometrial/inducido químicamente , Hiperplasia Endometrial/patología , Hiperplasia Endometrial/metabolismo , Progesterona/sangre , Dieta , Estradiol/sangre , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genéticaRESUMEN
Dipyrone is a commonly used analgesic in many countries and there is limited data on its possible endocrine disrupting effects. We performed a screening for in vivo and in vitro anti(estrogenic) activity of dipyrone. For the in vivo uterotrophic assay, immature female rats (22-days-old) were treated daily by oral gavage for three days with different doses of dipyrone alone (50, 100, 200 mg/kg/day) and associated with three ethynylestradiol (EE) doses (1, 3 and 10 µg/kg/day), which were based on a dose-response curve experiment. The uterine weight was used as a biomarker for estrogenicity. In a parallel in vitro approach, we used a yeast-based transcriptional activation reporter gene assay (Yeast Estrogen Screening - YES) for assessment of estrogenic agonistic and antagonistic effects of dipyrone and its main metabolites 4-methylaminoantipyrine (MAA) and 4-aminoantipyrine (AA). In the uterotrophic assay, animals that received EE at 1, 3 and 10 µg/kg/day showed an increase in relative uterine weight compared with vehicle-only rats (canola oil). Dipyrone did not increase uterine weight at any dose tested (50, 100 and 200 mg/kg/day) in relation to vehicle control, indicating absence of estrogenic activity. Furthermore, co-administration of dipyrone (50 and 200 mg/kg/day) and EE (1, 3 or 10 µg/kg/day) was unable to block EE estrogenic action in comparison to the groups treated with EE alone, indicating absence of antiestrogenic activity. In the YES assay dipyrone and its metabolites did not demonstrate estrogen agonistic or antagonistic properties in the yeast cells. These results suggest that dipyrone and its metabolites do not produce (anti)estrogenic effects in vivo or in vitro.
Asunto(s)
Antiinflamatorios no Esteroideos/toxicidad , Dipirona/toxicidad , Estrógenos/toxicidad , Útero/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Dipirona/administración & dosificación , Relación Dosis-Respuesta a Droga , Estrógenos/administración & dosificación , Femenino , Ratas , Ratas Wistar , Saccharomyces cerevisiaeRESUMEN
Chlorpyrifos (CPF), the most used insecticide in Argentina, can act as an endocrine disruptor at low doses. We previously demonstrated that chronic exposure to CPF induces hormonal imbalance in vivo. The aim of this work was to study the effects of low concentrations of CPF (0.01 and 1 mg/kg/day) on the reproductive system of virgin adult rats. In the ovary, we studied the effects of CPF on steroidogenesis by determining steroid hormone content by RIA and CYP11 and CYP19 enzyme expression by qRT-PCR. The estrous cycle was evaluated by microscopic observation of vaginal smear, as well as by changes in uterine histology. In endometrium, we determined the fractal dimension and expression of PCNA, ERα and PR by IHC. Our results showed that chronic exposure to CPF affects ovarian steroid synthesis, causing alterations in the normal cyclicity of animals. In addition, CPF induced proliferative changes in the uterus, suggesting that it could affect reproduction or act as a risk factor in the development of uterine proliferative pathologies.
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Cloropirifos/administración & dosificación , Cloropirifos/toxicidad , Ciclo Estral/efectos de los fármacos , Ovario/efectos de los fármacos , Útero/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Insecticidas/administración & dosificación , Insecticidas/toxicidad , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Vagina/efectos de los fármacosRESUMEN
Although progesterone has the ability to promote dilation of vascular smooth muscle, its role in coronary circulation is still poorly characterized, especially in essential hypertension and in a model of endogenous deficiency of ovarian hormones. Thus, this study evaluated the effect of progesterone treatment on endothelium-dependent coronary vascular reactivity in hypertensive (SHR) and ovariectomized rats. Adult SHR aged 8-10 weeks were divided into: SHAM, Ovariectomized (OVX) and Ovariectomized + treatment with 2 mg/kg/day of progesterone for 15 days (OVX-P4). Coronary vascular reactivity was investigated using the modified Langendorff method. After stabilization, baseline coronary perfusion pressure (CPP) was recorded and vascular reactivity to bradykinin (BK, 0.1-1000 ng) were assessed before and after infusion, either individually or in combination, with Nω-nitro-l-arginine methyl ester (l-NAME), indomethacin or clotrimazole. Scanning electron microscopy was used for qualitative analysis of the endothelium. OVX and OVX-P4 groups had a higher baseline CPP compared to that of the SHAM group. BK was able to promote vasodilation in all groups. However, relaxation to BK was less pronounced in the OVX group when compared to SHAM, with architecture loss and areas of cell atrophy having been observed. Progesterone treatment prevented this injury. Perfusion with l-NAME induced greater damage to the SHAM group, while the use of indomethacin led to a significant reduction in the vasodilator response to BK in the OVX-P4 group. Taken together, our results show that progesterone modulates endothelium-dependent coronary vasodilation in SHR ovariectomized, preventing damage caused by ovarian hormonal deficiency through a mechanism that involves prostanoid pathway.
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Vasos Coronarios/patología , Endotelio Vascular/patología , Hipertensión/patología , Progesterona/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Bradiquinina/farmacología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/ultraestructura , Endotelio Vascular/efectos de los fármacos , Femenino , Tamaño de los Órganos/efectos de los fármacos , Perfusión , Ratas Endogámicas SHR , Sístole/efectos de los fármacos , Útero/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
The developing uterus is highly sensitive to a brief exposure to different substances, in particular those with endocrine-disrupting activity. Thus, exposure to environmental, nutritional, chemical, and other xenobiotic factors affecting signaling events during critical organizational periods can alter the normal course of uterine development with lasting consequences. In this chapter, we provide an experimental protocol to evaluate the development of the rat uterus as a toxicity biomarker at two different developmental time points: (1) the neonatal period, on postnatal day (PND) 8, and (2) the prepubertal period, on PND21. In this experimental approach, we propose to assess: (1) uterine morphology and cytodifferentiation, (2) uterine cell proliferation, and (3) the expression of proteins involved in uterine organogenetic differentiation. All these morphological and molecular markers are useful tools to determine the consequences of exposure to toxicants with the potential to disrupt the uterine development.
Asunto(s)
Pruebas de Toxicidad , Útero/efectos de los fármacos , Factores de Edad , Animales , Animales Recién Nacidos , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Inmunohistoquímica , Microscopía , Organogénesis/efectos de los fármacos , Embarazo , Ratas , Ratas Wistar , Útero/metabolismo , Útero/patologíaRESUMEN
The essential oil of Lippia microphylla (LM-OE) presents several pharmacological activities. This work evaluates the tocolytic effect of LM-OE on rats. LM-OE inhibited phasic contractions and relaxed tonic contractions on rat uterus. Considering that nitric oxide (NO) pathway regulates uterine contraction, LM-OE potency was attenuated in the presence of NO synthase (NOS) inhibitor and this reduction was reversed in the presence of a NOS substrate. Similarly, the relaxant potency of LM-OE was reduced in the presence of soluble guanylyl cyclase (sGC) and protein kinase G (PKG) inhibitors. LM-OE also demonstrates a positive modulation of large and small conductance calcium-activated, voltage-gated and adenosine triphosphate-sensitive potassium channels and inhibited curves to CaCl2 as well as relaxed the uterus pre-contracted by S-(-)-Bay K8644, suggesting voltage-gated calcium channels type-1 (CaV1) blockade. Thus, the tocolytic effect of LM-OE on rat involves positive modulation of NO/NOS/sGC/PKG/K+-channels pathway and Ca2+ influx blockade through CaV1.[Formula: see text].
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Calcio/metabolismo , Lippia/química , Óxido Nítrico/metabolismo , Aceites Volátiles/farmacología , Transducción de Señal , Tocolíticos/farmacología , Útero/efectos de los fármacos , Animales , Femenino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Oxitocina/farmacología , Canales de Potasio/metabolismo , Cloruro de Potasio/farmacología , Ratas , Transducción de Señal/efectos de los fármacos , Contracción Uterina/efectos de los fármacos , Útero/metabolismoRESUMEN
AIM: Although soy isoflavones (ISO) have been shown to relief postmenopausal symptoms, it remains inconclusive whether ISO can improve lipid-profile without uterotrophic effects under estrogen-deficiency. Thus, we investigated the effects of ISO on lipid-profile and uterus of ovariectomized (Ovx) rats. MATERIALS AND METHODS: Twenty-five adult rats were Ovx or Sham-operated (Sham) and assigned into five groups: Sham and Ovx groups, administered with vehicle solutions; Ovx-E, treated with 10 µg/kg of 17ß-Estradiol; Ovx-ISO, treated with 200 mg/kg of ISO; Ovx-E + ISO, treated with estradiol + ISO combined. After fifty days of treatments, rats were euthanized and uterine horns were processed for histomorphometry or to collagen fibers and glycosaminoglycans evaluations. Blood samples were collected to evaluate levels of triglycerides, total cholesterol (TC) and its fractions (HDL/VLDL). Data were subjected to statistical analysis (p < .05). RESULTS: Uterus weight was lower in Ovx group than the Sham and Ovx-E groups, whereas it was similar between Ovx and Ovx-ISO groups. Histomorphometry showed atrophic uterus in Ovx and Ovx-ISO groups, whereas uterotrophic effects were noticed in Ovx-E and Ovx-E + ISO groups. Collagen fibers-birefringence was higher in Sham, Ovx, and Ovx-ISO groups than in Ovx-E and Ovx-E + ISO groups. Sulfated glycosaminoglycans content was similar among Sham, Ovx, and Ovx-ISO groups, while it was higher in estrogen-treated groups; total glycosaminoglycans content was similar among groups. TC and HDL was higher in Ovx-ISO group, whereas VLDL and triglycerides levels was higher in Ovx-E + ISO group and similar among other groups. CONCLUSION: Soy isoflavones at 200 mg/kg have slight beneficial effects on lipid-profile without uterotrophic effects in Ovx rats.
Asunto(s)
Glycine max , Isoflavonas/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Fitoterapia , Útero/efectos de los fármacos , Animales , Evaluación Preclínica de Medicamentos , Femenino , Colágenos Fibrilares/metabolismo , Glicosaminoglicanos/metabolismo , Isoflavonas/farmacología , Ovariectomía , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ratas Wistar , Útero/metabolismoRESUMEN
Treatment with estrogens alone in women without a uterus or in combination with progestins (PG) in women with a uterus is the most effective treatment for vasomotor symptoms in the peri or postmenopausal period. However, PGs differ by their biological activities, and it is likely that not all PGs will display a class effect. The type of PG is important regarding tolerance and cardiovascular and breast cancer risk. Some studies indicate that micronized progesterone (P) is safer than synthetic PGs with an acceptable metabolic profile. For that purpose, we conducted a narrative review on the balance between benefit/risk using P versus PGs in menopause hormone therapy (MHT) to aid clinician to choose the best regimens, specifically the PG component of hormone therapy, for women with bothersome menopausal symptoms and with a uterus.
Asunto(s)
Neoplasias de la Mama/inducido químicamente , Terapia de Reemplazo de Hormonas/métodos , Progesterona/uso terapéutico , Progestinas/uso terapéutico , Mama/efectos de los fármacos , Mama/fisiología , Enfermedades Cardiovasculares/prevención & control , Terapia de Reemplazo de Estrógeno/métodos , Femenino , Terapia de Reemplazo de Hormonas/efectos adversos , Humanos , Menopausia , Persona de Mediana Edad , Perimenopausia , Posmenopausia , Progesterona/administración & dosificación , Progesterona/efectos adversos , Progestinas/administración & dosificación , Progestinas/efectos adversos , Medición de Riesgo , Útero/efectos de los fármacos , Sistema Vasomotor/efectos de los fármacosRESUMEN
OBJECTIVE: To evaluate the effect of a herbal preparation containing glucosinolates, phytosterols and citrus flavonoids (supplement) on body weight and metabolic parameters usually impaired by menopause. METHODS: A pre-clinical experimental study carried out in twenty-five Swiss strain mice (Mus musculus) randomly distributed (1:1:1:1:1 ratio) to five groups to receive for ten weeks: (1) oral gelatinized maca extract 0.5625 mg/kg/day + bilateral ovariectomy (Maca + OVX); (2) oral supplement 0.5625 mg/kg/day + bilateral ovariectomy (S1 + OVX); (3) oral supplement 1.6875 mg/kg/day + bilateral ovariectomy (S2 + OVX); (4) oral saline 100 µl/kg/day + bilateral ovariectomy (OVX); and (5) oral saline 100 µl/kg/day + sham surgery (sham). The primary endpoint was change in body weight gain from baseline to final. Secondary endpoints were uterine weight and cholesterol, triglyceride, glucose, and glucose/triglycerides index values at the end of the study. A modified intention-to-treat analysis was performed through linear regression models and using the Bonferroni method to penalized p-values by multiple comparisons. RESULTS: Twenty-three animals completed the study. There was a significant average difference in weight gain, with a greater reduction in the S2 + OVX group compared to the OVX group (difference= -3.5; 95% CI (-5.27; -1.74); p < .001). S2 + OVX group also displayed a significant average reduction of total blood cholesterol (difference: -16.94; 95% CI (-33.73; -0.15); p = .037). No significant effects of the supplement were found on other secondary endpoints. CONCLUSION: In this murine menopausal model, triple oral supplement dose resulted in an average reduction of weight gain and total cholesterol levels, suggesting that the compound could have a potential effect at regulating menopausal altered metabolism.
Asunto(s)
Glucosinolatos/farmacología , Hesperidina/farmacología , Lepidium , Menopausia , Ovariectomía , Fitosteroles/farmacología , Preparaciones de Plantas/farmacología , Aumento de Peso/efectos de los fármacos , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Colesterol/sangre , Suplementos Dietéticos , Femenino , Ratones , Tamaño de los Órganos , Extractos Vegetales/farmacología , Sitoesteroles/farmacología , Triglicéridos/sangre , Útero/efectos de los fármacos , Útero/patologíaRESUMEN
Caffeic acid is a phenolic compound widely found in commonly consumed foods such as pears, apples and coffee, and is pharmacologically known for its antioxidant, anti-inflammatory and anti-asthmatic properties. However, its relaxant activity in the aorta, uterus and ileum smooth muscle has not been investigated. This study aimed to comparatively evaluate the effect of caffeic acid on smooth muscle from different organs (aorta, uterus and ileum), and the contractions of this different organ were induced by different agonists. The organ bath technique was used, where the organs were placed in different cuvettes with 10 mL of Tyrode solution for 1 h to stabilize, then, myometrial, intestinal strip and aortic ring contractions were evoked using different contractile agonists (KCl 60 mM, PHE 0.1 µM, OT 10-2 IU/mL, CCh 10-6 M and BaCl2 0.1-30 mM); increasing concentrations of caffeic acid (0.03-7 mM) were administered in the experimental preparations. In the presence of KCl (60 mM), caffeic acid caused relaxations with the following EC50 values: 2.7 ± 0.26 mM/mL (aorta), 5.7 ± 0.71 mM/mL (uterus) and 2.1 ± 0.39 mM/mL (ileum). When in the presence of different agonists, PHE (0.1 µM) for the aorta, OT (10-2 IU/mL) for the uterus and CCh (10-6 M) for the ileum, caffeic acid caused relaxations with EC50 values of: 2.7 ± 0.31 mM/mL; 2.2 ± 0.34 mM/mL and 2.0 ± 0.28 mM/mL, respectively. The inhibitory effect of caffeic acid on serotonergic (aorta and uterus) and muscarinic receptors (uterus and ileum), as well as its possible involvement with L-type Ca2+ channels, was also observed. This study reports the pharmacological characterization of caffeic acid on smooth muscle from different organs, for which caffeic acid was more potent in the ileum. A diverse understanding of its performance as a possible therapeutic product is attributed to its relaxant effect.
Asunto(s)
Aorta/fisiología , Ácidos Cafeicos/farmacología , Evaluación Preclínica de Medicamentos , Íleon/fisiología , Músculo Liso/fisiología , Fenoles/farmacología , Útero/fisiología , Animales , Aorta/efectos de los fármacos , Ácidos Cafeicos/química , Canales de Calcio Tipo L/metabolismo , Carbacol/farmacología , Femenino , Íleon/efectos de los fármacos , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Oxitocina/farmacología , Fenoles/química , Fenilefrina/farmacología , Cloruro de Potasio , Ratas Wistar , Útero/efectos de los fármacosRESUMEN
Polycystic ovary syndrome (PCOS) is associated with hyperandrogenemia and uterine abnormalities. Our aim was to investigate the uterine effects of PCOS that are mediated through the androgen receptor (AR). After weaning, female rats were treated with sesame oil (Control), dehydroepiandrosterone (DHEA), or DHEA + flutamide (FLU, an AR antagonist) for 20 consecutive days. On postnatal day 41, serum, ovarian and uterine tissues were collected. DHEA and DHEA + FLU rats showed increased testosterone levels. DHEA rats showed increased epithelial height, glandular density, subepithelial stroma and myometrial thickness, associated with decreased nuclei density. These rats also showed increased uterine water content, with decreased aquaporin (AQP) 3, 7 and 8 expression in the uterine epithelium and increased AQP8 expression in the myometrium. DHEA rats also showed decreased uterine collagen remodeling, decreased cell proliferation in the subepithelial stroma, and increased apoptosis in the luminal and glandular epithelium and in the myometrium. They also showed an increase in insulin-like growth factor-1 and a decrease in phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. The uterine stroma of DHEA rats showed no changes in progesterone receptor or estrogen receptor alpha (ERα) and increased AR expression. DHEA + FLU rats showed a smaller increase in the myometrial thickness, an increase in the uterine water content without AQP8 induction and a smaller decrease in collagen remodeling. These rats also showed no apoptosis induction and decreased proliferation in the myometrium, decreased ERα in the subepithelial stroma and myometrium and no modifications in AR. Our results demonstrate that the uterine cell turnover and collagen remodeling in DHEA rats are regulated through AR, directly or indirectly associated with ERα expression.
Asunto(s)
Deshidroepiandrosterona/efectos adversos , Receptor alfa de Estrógeno/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Receptores Androgénicos/metabolismo , Útero/patología , Animales , Animales Recién Nacidos , Acuaporinas/metabolismo , Colágeno/metabolismo , Modelos Animales de Enfermedad , Femenino , Flutamida/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Síndrome del Ovario Poliquístico/inducido químicamente , Ratas , Testosterona/sangre , Testosterona/metabolismo , Útero/efectos de los fármacos , Útero/metabolismoRESUMEN
Changes in circulating progesterone (P4) and estradiol (E2) during proestrus produce dynamic changes in endometrial function and pituitary release of gonadotropins. Independent and combined effects of P4 and E2 on endometrium and pituitary were evaluated. In a preliminary study, an exogenous hormone model of proestrus was created by removal of corpus luteum and follicles ≥5 mm followed by gradual removal of intravaginal P4 implants during 18 h and treatment with increasing doses of estradiol benzoate during 48 h to mimic proestrus using high E2 (n = 9) or low E2 (n = 9). Decreased P4, increased E2, and increased endometrial area (EA) simulated proestrus in high-E2 cows and this was used subsequently. The main experiment used a 2 × 2 factorial design with: high E2 and low P4 (n = 11); high E2 and high P4 (n = 11); low E2 and high P4 (n = 11); low E2 and low P4 (n = 10). At 48 h, gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) and follicle stimulating hormone (FSH) release was determined. Variables were analyzed using PROCMIXED of Statistical Analysis System. The EA increased dramatically during 48 h only in high-E2 and low-P4 cows. For FSH, high-E2 cows had greater area under the curve (AUC) and FSH peak after GnRH than low E2, with mild negative effects of high P4. For LH, concentration at peak and AUC were 2-fold greater in high E2 compared to low-E2 groups, with low P4 also 2-fold greater than high-P4 groups. Thus, maximal changes in uterus and pituitary during proestrus depend on both low P4 and high E2, but different physiologic responses are regulated differently by E2 and P4. Changes in endometrium depend on low P4 and high E2, whereas GnRH-induced FSH secretion primarily depends on high E2, and GnRH-induced LH secretion is independently increased by high E2 or reduced by high P4.