RESUMEN
Cranial radiotherapy induces endocrine disorders and reproductive abnormalities, particularly in long-term female cancer survivors, and this might in part be caused by injury to the pituitary gland, but the underlying mechanisms are unknown. The aim of this study was to investigate the influence of cranial irradiation on the pituitary gland and related endocrine function. Female Wistar rat pups on postnatal day 11 were subjected to a single dose of 6 Gy whole-head irradiation, and hormone levels and organ structure in the reproductive system were examined at 20 weeks after irradiation. We found that brain irradiation reduced cell proliferation and induced persistent inflammation in the pituitary gland. The whole transcriptome analysis of the pituitary gland revealed that apoptosis and inflammation-related pathways were up-regulated after irradiation. In addition, irradiation led to significantly decreased levels of the pituitary hormones, growth hormone, adrenocorticotropic hormone, thyroid-stimulating hormone and the reproductive hormones testosterone and progesterone. To conclude, brain radiation induces reduction of pituitary and reproduction-related hormone secretion, this may due to reduced cell proliferation and increased pituitary inflammation after irradiation. Our results thus provide additional insight into the molecular mechanisms underlying complications after head irradiation and contribute to the discovery of preventive and therapeutic strategies related to brain injury following irradiation.
Asunto(s)
Irradiación Craneana , Hipopituitarismo/etiología , Hipopituitarismo/metabolismo , Hipófisis/metabolismo , Hipófisis/efectos de la radiación , Hormonas Hipofisarias/biosíntesis , Hormona Adrenocorticotrópica/biosíntesis , Animales , Biomarcadores , Proliferación Celular/efectos de la radiación , Biología Computacional/métodos , Irradiación Craneana/efectos adversos , Modelos Animales de Enfermedad , Ciclo Estral/efectos de la radiación , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de la radiación , Hipopituitarismo/patología , Inmunohistoquímica , Hipófisis/patología , Hormonas Hipofisarias/deficiencia , Traumatismos por Radiación/complicaciones , Ratas , Transducción de Señal/efectos de la radiación , Transcriptoma , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Background Human reproduction depends on the fusion of a mature oocyte with a sperm cell to form a fertilized egg. The genetic events that lead to the arrest of human oocyte maturation are unknown. Methods We sequenced the exomes of five members of a four-generation family, three of whom had infertility due to oocyte meiosis I arrest. We performed Sanger sequencing of a candidate gene, TUBB8, in DNA samples from these members, additional family members, and members of 23 other affected families. The expression of TUBB8 and all other ß-tubulin isotypes was assessed in human oocytes, early embryos, sperm cells, and several somatic tissues by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay. We evaluated the effect of the TUBB8 mutations on the assembly of the heterodimer consisting of one α-tubulin polypeptide and one ß-tubulin polypeptide (α/ß-tubulin heterodimer) in vitro, on microtubule architecture in HeLa cells, on microtubule dynamics in yeast cells, and on spindle assembly in mouse and human oocytes. Results We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families. TUBB8 expression is unique to oocytes and the early embryo, in which this gene accounts for almost all the expressed ß-tubulin. The mutations affect chaperone-dependent folding and assembly of the α/ß-tubulin heterodimer, disrupt microtubule behavior on expression in cultured cells, alter microtubule dynamics in vivo, and cause catastrophic spindle-assembly defects and maturation arrest on expression in mouse and human oocytes. Conclusions TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility. (Funded by the National Basic Research Program of China and others.).
Asunto(s)
Infertilidad Femenina/genética , Meiosis/genética , Microtúbulos/patología , Mutación , Oocitos/fisiología , Huso Acromático/fisiología , Tubulina (Proteína)/genética , Adulto , Animales , Femenino , Humanos , Meiosis/fisiología , Ratones , Microtúbulos/fisiología , ARNRESUMEN
Glucagon-like peptide 1 (GLP-1), produced in the intestine and the brain, can stimulate insulin secretion from the pancreas and alleviate type 2 diabetes. The cytokine interleukin-6 (IL-6) may enhance insulin secretion from ß-cells by stimulating peripheral GLP-1 production. GLP-1 and its analogs also reduce food intake and body weight, clinically beneficial actions that are likely exerted at the level of the CNS, but otherwise are poorly understood. The cytokines IL-6 and interleukin 1ß (IL-1ß) may exert an anti-obesity effect in the CNS during health. Here we found that central injection of a clinically used GLP-1 receptor agonist, exendin-4, potently increased the expression of IL-6 in the hypothalamus (11-fold) and the hindbrain (4-fold) and of IL-1ß in the hypothalamus, without changing the expression of other inflammation-associated genes. Furthermore, hypothalamic and hindbrain interleukin-associated intracellular signals [phosphorylated signal transducer and activator of transcription-3 (pSTAT3) and suppressor of cytokine signaling-1 (SOCS1)] were also elevated by exendin-4. Pharmacologic disruption of CNS IL-1 receptor or IL-6 biological activity attenuated anorexia and body weight loss induced by central exendin-4 administration in a rat. Simultaneous blockade of IL-1 and IL-6 activity led to a more potent attenuation of exendin-4 effects on food intake. Mice with global IL-1 receptor gene knockout or central IL-6 receptor knockdown showed attenuated decrease in food intake and body weight in response to peripheral exendin-4 treatment. GLP-1 receptor activation in the mouse neuronal Neuro2A cell line also resulted in increased IL-6 expression. These data outline a previously unidentified role of the central IL-1 and IL-6 in mediating the anorexic and body weight loss effects of GLP-1 receptor activation.
Asunto(s)
Regulación del Apetito/fisiología , Peso Corporal/fisiología , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Obesidad/metabolismo , Receptores de Glucagón/metabolismo , Análisis de Varianza , Animales , Western Blotting , Técnicas de Silenciamiento del Gen , Receptor del Péptido 1 Similar al Glucagón , Masculino , Ratones , Ratones Noqueados , Ratas , Ratas Sprague-Dawley , Receptores de Interleucina-1/genéticaRESUMEN
BACKGROUND: The fallopian tube transports the gametes to the fertilization site and delivers the embryo to the uterus at the optimal time for implantation. Progesterone and the classical progesterone receptor are involved in regulating both tubal ciliary beating and muscular contractions, likely via both genomic and non-genomic actions. METHODS: To provide more details of the underlying mechanisms, we investigated the effect of progesterone on gene expression in mice fallopian tubes in vitro at 20 min, 2 h and 8 h post progesterone treatment using microarray and/or quantitative PCR. In parallel, oocyte cumulus complex transport was investigated in ovulating mice that were injected with one of the progesterone receptor antagonists, Org 31710 or CDB2194. RESULTS: Microarray analyses did not reveal any apparently regulated genes 20 min after progesterone treatment, consistent with the proposed non-genomic action of progesterone controlling ciliary beating. After 2 h, 11 genes were identified as up-regulated. Analyses using quantitative PCR at 2 h and 8 h showed a consistent up-regulation of endothelin1 and a down-regulation of its receptor Endothelin receptor A by progesterone. We also confirmed that treatment with progesterone receptor antagonists before ovulation accelerates the transport of the oocyte cumulus complex. CONCLUSIONS: This is the first study showing that progesterone regulates the expression of endothelin1 and endothelin receptor A in the fallopian tube. Together with previous studies of the effects of endothelin on muscular contractions in the fallopian tube, the results from this study suggest that endothelin is a mediator of the progesterone-controlled effects on muscular contraction and eventually gamete transport in the fallopian tube.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Células del Cúmulo/metabolismo , Trompas Uterinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Oocitos/metabolismo , Progesterona/farmacología , Animales , Movimiento Celular/fisiología , Trompas Uterinas/fisiología , Femenino , Ratones , Ratones Endogámicos C57BL , Progesterona/fisiologíaRESUMEN
Polycystic ovary syndrome (PCOS) is a state of altered steroid hormone production and activity. Chronic estrogen exposure or lack of progesterone due to ovarian dysfunction can result in endometrial hyperplasia and carcinoma. A key contributor to our understanding of progesterone as a critical regulator for normal uterine function has been the elucidation of progesterone receptor (PR) expression, regulation, and signaling pathways. Several human studies indicate that PR-mediated signaling pathways in the nucleus are associated with progesterone resistance in women with PCOS. The aim of this review is to provide an overview of endometrial progesterone resistance in women with PCOS; to present the PR structure, its different isoforms, and their expression in the endometrium; to illustrate the possible regulation of PR and PR-mediated signaling in progesterone resistance in women with PCOS; and to discuss current clinical treatments for atypical endometrial hyperplasia and endometrial carcinoma in women with PCOS and accompanying progesterone resistance.
Asunto(s)
Endometrio/anomalías , Síndrome del Ovario Poliquístico/genética , Progesterona/biosíntesis , Progesterona/genética , Enfermedades Uterinas/genética , Hiperplasia Endometrial/genética , Hiperplasia Endometrial/patología , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Regulación de la Expresión Génica , Humanos , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/patología , Progesterona/metabolismo , Transducción de SeñalRESUMEN
Nitric oxide (NO) is highly unstable and has a half-life of seconds in buffer solutions. It is synthesized by NO-synthase (NOS), which has been found to exist in the following three isoforms: neuro nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS). NOS activity is localized in the reproductive tracts of many species, although direct evidence for NOS isoforms in the Fallopian tubes of mice is still lacking. In the present study, we investigated the expression and regulation of NOS isoforms in the mouse and human Fallopian tubes during the estrous and menstrual cycles, respectively. We also measured isoform expression in humans with ectopic pregnancy and in mice treated with lipopolysaccharide (LPS). Our results confirmed the presence of different NOS isoforms in the mouse and human Fallopian tubes during different stages of the estrous and menstrual cycles and showed that iNOS expression increased in the Fallopian tubes of women with ectopic pregnancy and in LPS-treated mice. Elevated iNOS activity might influence ovulation, cilia beats, contractility, and embryo transportation in such a manner as to increase the risk of ectopic pregnancy. This study has provided morphological and molecular evidence that NOS isoforms are present and active in the human and mouse Fallopian tubes and suggests that iNOS might play an important role in both the reproductive cycle and infection-induced ectopic pregnancies.
Asunto(s)
Trompas Uterinas/enzimología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Embarazo Ectópico/enzimología , Adulto , Animales , Ciclo Estral , Femenino , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Ciclo Menstrual , Ratones , Ratones Endogámicos , Óxido Nítrico Sintasa de Tipo II/genética , EmbarazoRESUMEN
Deoxynivalenol (DON), a mycotoxin produced by Fusarium, poses a significant risk to human health and the environment. Therefore, the development of a highly sensitive and accurate detection method is essential to monitor the pollution situation. In response to this imperative, we have devised an advanced split-type photoelectrochemical (PEC) sensor for DON analysis, which leverages self-shedding MOF-nanocarriers to modulate the photoelectric response ability of PEC substrate. The PEC sensing interface was constructed using CdS/MoSe2 heterostructures, while the self-shedding copper peroxide nanodots@ZIF-8 (CPNs@ZIF-8) served as the Cu2+ source for the in-situ ion exchange reaction, which generated a target-related signal reduction. The constructed PEC sensor exhibited a broad linear range of 0.1 pg mL-1 to 500 ng mL-1 with a low detection limit of 0.038 pg mL-1, demonstrating high stability, selectivity, and proactivity. This work not only introduces innovative ideas for the design of photosensitive materials, but also presents novel sensing strategies for detecting various environmental pollutants.
Asunto(s)
Compuestos de Cadmio , Técnicas Electroquímicas , Estructuras Metalorgánicas , Tricotecenos , Tricotecenos/análisis , Tricotecenos/química , Técnicas Electroquímicas/métodos , Compuestos de Cadmio/química , Estructuras Metalorgánicas/química , Sulfuros/química , Límite de Detección , Procesos Fotoquímicos , Intercambio IónicoRESUMEN
BACKGROUND: Several peripheral proteins that might be useful for detecting the presence of ectopic pregnancy (EP) have been evaluated, but none have been proven entirely useful in the clinic. We investigated the presence and the possible changes in circulating molecules that distinguish between normal intrauterine pregnancy (IUP) and tubal ectopic pregnancy. METHODS: Non-pregnant women during the menstrual cycle, women with IUP, and women with tubal EP after informed consent. Serum levels of 17ß-estradiol (E2), progesterone (P4), testosterone (T), beta-human chorionic gonadotropin (ß-hCG), vascular endothelial growth factor-A (VEGF-A), placental growth factor (PIGF), and a distintegrin and metalloprotease protein 12 (ADAM12) were analyzed. Receiver operating characteristic analysis was used to assess the diagnostic discrimination of EP and gestational age-matched IUP. RESULTS: E2, P4, PIGF, and ADAM12 levels increased and ß-hCG decreased throughout IUP. E2 and VEGF-A levels were significantly different between women with tubal EP and IUP. However, using a serum ß-hCG cut-off of less than 1000 mIU/mL, P4 was significantly lower in women with tubal EP compared to IUP. Although E2 was inversely correlated with VEGF-A in women in the early stages of IUP, E2 was not correlated with VEGF-A in women with EP prior to tubal surgery. There were no significant differences in either PIGF or ADAM12 alone between women with tubal EP or IUP. Although no significant correlations were seen between E2 and PIGF or P4 and ADAM12 in women in the early stages of IUP, E2 was positively correlated with PIGF and P4 was positively correlated with ADAM12 in women with EP prior to tubal surgery. Our studies defined associations but not causality. CONCLUSIONS: Individual measurements of serum E2 or VEGF-A levels are strongly related to early pregnancy outcomes for women with IUP and EP, and pregnancy-associated E2 and VEGF-A levels provide diagnostic accuracy for the presence of tubal EP. This study demonstrates that correlation analysis of E2/VEGF-A and E2/PIGF serum levels may be able to distinguish a tubal EP from a normal IUP.
Asunto(s)
Proteínas ADAM/sangre , Hormonas Esteroides Gonadales/sangre , Proteínas de la Membrana/sangre , Proteínas Gestacionales/sangre , Embarazo Ectópico/diagnóstico , Factor A de Crecimiento Endotelial Vascular/sangre , Proteína ADAM12 , Femenino , Humanos , Ciclo Menstrual , Factor de Crecimiento Placentario , Embarazo , Embarazo Ectópico/sangreRESUMEN
Heterogeneous nuclear ribonucleoproteins (hnRNPs), which are chromatin-associated RNA-binding proteins, participate in mRNA stability, transport, intracellular localization, and translation by acting as transacting factors. Several studies have shown that steroid hormones can regulate hnRNP expression. However, to date, the regulation of hnRNPs and their interactions with steroid hormone signaling in fallopian tubes and endometrium are not fully elucidated. In the present study, we determined whether hnRNP expression is regulated during the menstrual cycle and correlates with estrogen receptor (ER) and progesterone receptor (PR) levels in human fallopian tubes in vivo. Because of the limited availability of human tubal tissues for the research, we also explored the mechanisms of hnRNP regulation in human endometrium in vitro. Fallopian tissue was obtained from patients in the early, late, and postovulatory phases and the midsecretory phase and endometrial tissue from premenopausal and postmenopausal women undergoing hysterectomy. We measured expression of hnRNPs and assessed their intracellular localization and interactions with ERs and PRs. We also determined the effects of human chorionic gonadotropin, 17ß-estradiol (E(2)), and progesterone (P(4)) on hnRNP expression. In fallopian tubes, mRNA and protein levels of hnRNP A1, AB, D, G, H, and U changed dynamically during ovulation and in the midsecretory phase. In coimmunolocation and coimmunoprecipitation experiments, hnRNPs interacted with each other and with ERs and PRs in fallopian tubes. After treatment with E(2) and/or P(4) to activate ERs and PRs, hnRNP A1, AB, D, G, and U proteins displayed overlapping but distinct patterns of regulation in the endometrium in vitro. Our findings expand the physiological repertoire of hnRNPs in human fallopian tubes and endometrium and suggest that steroid hormones regulate different hnRNPs directly by interacting with ERs and/or PRs or indirectly by binding other hnRNPs. Both actions may contribute to regulation of gene transcription.
Asunto(s)
Endometrio/fisiología , Trompas Uterinas/fisiología , Hormonas Esteroides Gonadales/metabolismo , Receptores de Esteroides/metabolismo , Ribonucleoproteínas Nucleares Pequeñas/metabolismo , Adulto , Gonadotropina Coriónica/metabolismo , Gonadotropina Coriónica/farmacología , Endometrio/efectos de los fármacos , Estradiol/metabolismo , Estradiol/farmacología , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Trompas Uterinas/efectos de los fármacos , Femenino , Hormonas Esteroides Gonadales/farmacología , Humanos , Técnicas In Vitro , Ciclo Menstrual/fisiología , Progesterona/metabolismo , Progesterona/farmacología , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Receptores de Esteroides/genética , Ribonucleoproteínas Nucleares Pequeñas/genéticaRESUMEN
Here, we tested the hypothesis that excess maternal androgen in late pregnancy reduces placental and fetal growth, increases placental steroidogenesis, and adversely affects glucose and lipid metabolism in adult female offspring. Pregnant Wistar rats were randomly assigned to treatment with testosterone (daily injections of 5 mg of free testosterone from gestational days 16 to 19) or vehicle alone. In experiment 1, fetal and placental weights, circulating maternal testosterone, estradiol, and corticosterone levels, and placental protein expression and distribution of estrogen receptor-α and -ß, androgen receptor, and 17ß-hydroxysteroid dehydrogenase 2 were determined. In experiment 2, birth weights, postnatal growth rates, circulating testosterone, estradiol, and corticosterone levels, insulin sensitivity, adipocyte size, lipid profiles, and the presence of nonalcoholic fatty liver were assessed in female adult offspring. Treatment with testosterone reduced placental and fetal weights and increased placental expression of all four proteins. The offspring of testosterone-treated dams were born with intrauterine growth restriction; however, at 6 wk of age there was no difference in body weight between the offspring of testosterone- and control-treated rats. At 10-11 wk of age, the offspring of the testosterone-treated dams had less fat mass and smaller adipocyte size than those born to control rats and had no difference in insulin sensitivity. Circulating triglyceride levels were higher in the offspring of testosterone-treated dams, and they developed nonalcoholic fatty liver as adults. We demonstrate for the first time that prenatal testosterone exposure alters placental steroidogenesis and leads to dysregulation of lipid metabolism in their adult female offspring.
Asunto(s)
Desarrollo Fetal/efectos de los fármacos , Retardo del Crecimiento Fetal/inducido químicamente , Hiperandrogenismo/sangre , Placenta/metabolismo , Efectos Tardíos de la Exposición Prenatal , Testosterona/sangre , Animales , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Estradiol Deshidrogenasas/efectos de los fármacos , Estradiol Deshidrogenasas/metabolismo , Ciclo Estral/efectos de los fármacos , Ciclo Estral/fisiología , Femenino , Insulina/fisiología , Intercambio Materno-Fetal , Placenta/efectos de los fármacos , Placentación , Embarazo , Distribución Aleatoria , Ratas , Ratas Wistar , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Testosterona/farmacologíaRESUMEN
Ectopic pregnancy (EP) is an enigmatic reproductive disorder. Although tubal EP is difficult to predict, several hypotheses about its etiology have been proposed. In retrospective case-control studies, smoking is associated with an increased rate of EPs in the fallopian tube. Studies of experimental animals in vivo and human fallopian tubal tissues in vitro have suggested mechanisms of fallopian tubal damage and dysfunction induced by nicotine and other smoking-related chemicals that may explain this association. However, the pathogenesis of smoking-induced modulation of implantation leading to tubal EP is largely unknown. Because cigarette/tobacco smoke adversely affects the success of intrauterine implantation, there is a great need to determine how embryo implantation occurs in the fallopian tube in female smokers of reproductive age.
Asunto(s)
Implantación del Embrión/fisiología , Trompas Uterinas/fisiopatología , Nicotina/efectos adversos , Agonistas Nicotínicos/efectos adversos , Embarazo Tubario/etiología , Fumar/efectos adversos , Contaminación por Humo de Tabaco/efectos adversos , Animales , Femenino , Humanos , Embarazo , Factores de RiesgoRESUMEN
Both low-frequency electro-acupuncture (EA) and manual acupuncture improve menstrual frequency and decrease circulating androgens in women with polycystic ovary syndrome (PCOS). We sought to determine whether low-frequency EA is more effective than manual stimulation in regulating disturbed oestrous cyclicity in rats with PCOS induced by 5α-dihydrotestosterone. To identify the central mechanisms of the effects of stimulation, we assessed hypothalamic mRNA expression of molecules that regulate reproductive and neuroendocrine function. From age 70 days, rats received 2 Hz EA or manual stimulation with the needles five times per week for 4-5 weeks; untreated rats served as control animals. Specific hypothalamic nuclei were obtained by laser microdissection, and mRNA expression was measured with TaqMan low-density arrays. Untreated rats were acyclic. During the last 2 weeks of treatment, seven of eight (88%) rats in the EA group had epithelial keratinocytes, demonstrating oestrous cycle change (P = 0.034 versus control rats). In the manual group, five of eight (62%) rats had oestrous cycle changes (n.s. versus control animals). The mRNA expression of the opioid receptors Oprk1 and Oprm1 in the hypothalamic arcuate nucleus was lower in the EA group than in untreated control rats. The mRNA expression of the steroid hormone receptors Esr2, Pgr and Kiss1r was lower in the manual group than in the control animals. In rats with 5α-dihydrotestosterone-induced PCOS, low-frequency EA restored disturbed oestrous cyclicity but did not differ from the manual stimulation group, although electrical stimulation lowered serum testosterone in responders, those with restored oestrus cyclicity, and differed from both control animals and the manual stimulation group. Thus, EA cannot in all aspects be considered superior to manual stimulation. The effects of low-frequency EA may be mediated by central opioid receptors, while manual stimulation may involve regulation of steroid hormone/peptide receptors.
Asunto(s)
Terapia por Acupuntura , Electroacupuntura , Ciclo Estral/fisiología , Síndrome del Ovario Poliquístico/fisiopatología , Animales , Núcleo Arqueado del Hipotálamo/fisiopatología , Dihidrotestosterona , Modelos Animales de Enfermedad , Femenino , Síndrome del Ovario Poliquístico/inducido químicamente , Progesterona/sangre , Ratas , Receptores Opioides kappa/biosíntesis , Receptores Opioides mu/biosíntesis , Testosterona/sangreRESUMEN
The causes of anxiety and depression in women with polycystic ovary syndrome (PCOS) remain elusive. To identify steps linking androgen signaling to the regulation of affective symptoms in vivo, we compared behavioral responses in female rats continuously exposed to DHT from puberty (a model of DHT-induced PCOS) and in rats exposed to DHT for 1week. Continuous and 1week of DHT exposure resulted in a general decrease in locomotor activity and time spent on the open arms in the elevated plus maze, indicating anxiety-like behavior. Rats with DHT-induced PCOS have increases in adiposity and circulating leptin levels accompanied by leptin resistance. One week of DHT exposure decreased androgen receptor (AR) expression in the hypothalamus and leptin synthesis and function in adipocytes; it also inhibited signal transducer and activator of transcription 3 (STAT3) and attenuated leptin activity by increasing levels of soluble leptin receptor, a leptin-binding protein, in the hypothalamus. This may affect the androgen-induced anxiety-related behavior in female rats. In conclusion, our results highlight the central role of androgens in behavioral function in female rats and suggest that androgens directly regulate the AR by decreasing its hypothalamic expression. Androgens also increase leptin synthesis in adipocytes, which drives central leptin signaling, and may regulate anxiety-related behaviors. Elucidating mechanisms by which androgens modulate female anxiety-like behavior may uncover useful approaches for treating women with PCOS who have symptoms of anxiety.
Asunto(s)
Andrógenos/farmacología , Conducta Animal/efectos de los fármacos , Fenómenos Fisiológicos Celulares/efectos de los fármacos , Leptina/farmacología , Animales , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Dihidrotestosterona , Modelos Animales de Enfermedad , Femenino , Humanos , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Tamaño de los Órganos/efectos de los fármacos , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/patología , Síndrome del Ovario Poliquístico/fisiopatología , Síndrome del Ovario Poliquístico/psicología , Ratas , Ratas Wistar , Receptores AndrogénicosRESUMEN
Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and insulin resistance, possibly reflecting defects in skeletal muscle and adipocyte insulin signaling. Low-frequency (2 Hz) electroacupuncture (EA) increases insulin sensitivity in female rats with dihydrotestosterone (DHT)-induced PCOS, but the mechanism is unclear. We hypothesized that low-frequency EA regulates mediators involved in skeletal muscle glucose uptake and metabolism and alters the lipid profile in rats with DHT-induced PCOS. To test this hypothesis, we implanted in prepubescent female rats 90-day continuous-release pellets containing DHT (PCOS). At 70 days of age, the rats were randomly subdivided into two groups: one received low-frequency EA (evoking muscle twitches) for 20-25 min five times/wk for 4-5 wk; the other did not. Controls were implanted with pellets containing vehicle only. All three groups were otherwise handled similarly. Lipid profile was measured in fasting blood samples. Insulin sensitivity was determined by euglycemic hyperinsulinemic clamp, soleus muscle protein expression of glucose transporter 4 (GLUT4), and phosphorylated and nonphosphorylated Akt, and Akt substrate of 160 kDa was determined by Western blot analysis and GLUT4 location by immunofluorescence staining. PCOS EA rats had normalized insulin sensitivity, lower levels of total high-density lipoprotein and low-density lipoprotein cholesterol, and increased expression of GLUT4 in different compartments of skeletal muscle compared with PCOS rats. Total weight and body composition did not differ in the groups. Thus, in rats with DHT-induced PCOS, low-frequency EA has systemic and local effects involving intracellular signaling pathways in muscle that may, at least in part, account for the marked improved insulin sensitivity.
Asunto(s)
Terapia por Acupuntura/métodos , Transportador de Glucosa de Tipo 4/metabolismo , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/fisiología , Músculo Esquelético/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/terapia , Animales , Western Blotting , Colesterol/sangre , Modelos Animales de Enfermedad , Femenino , Técnica del Anticuerpo Fluorescente , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Immunoblotting , Proteínas Proto-Oncogénicas c-akt/metabolismo , Distribución Aleatoria , Ratas , Ratas Wistar , Estadísticas no Paramétricas , Triglicéridos/sangreRESUMEN
Human ectopic pregnancy (EP) remains a common cause of pregnancy-related first trimester death. Nitric oxide (NO) is synthesized from L-arginine by three NO synthases (NOS) in different tissues, including the Fallopian tube. Studies of knockout mouse models have improved our understanding of the function of NOS isoforms in reproduction, but their roles and specific mechanisms in infection-induced tubal dysfunction have not been fully elucidated. Here, we provide an overview of the expression, regulation and possible function of NOS isoforms in the Fallopian tube, highlighting the effects of infection-induced changes in the tubal cellular microenvironment (imbalance of NO production) on tubal dysfunction and the potential involvement of NOS isoforms in tubal EP after Chlamydia trachomatis genital infection. The non-equivalent regulation of tubal NOS isoforms during the menstrual cycle suggests that endogenous ovarian steroid hormones regulate NOS in an isoform-specific manner. The current literature suggests that infection with C. trachomatis induces an inflammatory response that eventually leads to tubal epithelial destruction and functional impairment, caused by a high NO output mediated by inducible NOS (iNOS). Therefore, tissue-specific therapeutic approaches to suppress iNOS expression may help to prevent ectopic implantation in patients with prior C. trachomatis infection of the Fallopian tube.
Asunto(s)
Infecciones por Chlamydia/complicaciones , Chlamydia trachomatis , Trompas Uterinas/enzimología , Óxido Nítrico Sintasa/fisiología , Complicaciones Infecciosas del Embarazo/enzimología , Embarazo Ectópico/microbiología , Animales , Bovinos , Infecciones por Chlamydia/enzimología , Enfermedades de las Trompas Uterinas/enzimología , Enfermedades de las Trompas Uterinas/microbiología , Enfermedades de las Trompas Uterinas/patología , Trompas Uterinas/microbiología , Trompas Uterinas/patología , Femenino , Regulación de la Expresión Génica , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Isoenzimas/fisiología , Ratones , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Embarazo , Complicaciones Infecciosas del Embarazo/epidemiología , Complicaciones Infecciosas del Embarazo/microbiología , Embarazo Ectópico/enzimología , Embarazo Ectópico/epidemiología , RatasRESUMEN
Ectopic pregnancy, a worldwide health problem, is potentially life-threatening and occurs in approximately 1.5-2% of all pregnancies in the western world; however, the precise mechanisms underlying the initiation and development of tubal ectopic pregnancy are unknown. Tubal abnormalities and dysfunction, such as altered contractility or abnormal ciliary activity, have been speculated to lead to tubal ectopic pregnancy. To elucidate the cellular and molecular mechanisms of the tubal transport process, several knockout (KO) mouse models have been developed. This review summarizes what has been learned from studies of the Fallopian tube in caspase-1, cannabinoid receptor and Dicer1 KO mice. Our understanding of the mechanisms which contribute to tubal ectopic pregnancy in humans may be enhanced through further study of these KO mouse models.
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Trompas Uterinas/fisiología , Embarazo Ectópico/etiología , Animales , Moduladores de Receptores de Cannabinoides/fisiología , Caspasa 1/deficiencia , Caspasa 1/genética , Modelos Animales de Enfermedad , Estradiol/fisiología , Trompas Uterinas/fisiopatología , Femenino , Humanos , Ratones , Ratones Noqueados , Embarazo , Receptor Cannabinoide CB1/deficiencia , Receptor Cannabinoide CB1/genética , Ribonucleasa III/deficiencia , Ribonucleasa III/genéticaRESUMEN
OBJECTIVE: The purpose of this study was to investigate clomiphene citrate (CC)-induced modulation of uterine cell function in vivo. STUDY DESIGN: Prepubertal female Sprague-Dawley rats were treated intraperitoneally with CC for 6 or 24 hours or with a combination of CC and/or 17-beta-estradiol (E2) for 4 days. RESULTS: Chronic CC treatment induced apoptosis in a fraction of uterine stromal cells by activating the caspase-3-mediated apoptotic pathway. The damage was prevented by successive E2 treatment; however, pretreatment or concomitant treatment with E2 did not protect against CC-induced uterine apoptosis. CC decreased the protein expression of estrogen receptor alpha and increased its phosphorylation but did not affect estrogen receptor beta expression or phosphorylation. Furthermore, changes in Hoxa11, p27, and progesterone receptor protein levels and localization were associated with CC treatment. CONCLUSION: We provide novel mechanistic insights into cellular and molecular events by which CC regulates uterine stromal cell function and hence the implantation process and pregnancy outcome.
Asunto(s)
Apoptosis/fisiología , Clomifeno/farmacología , Estradiol/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Útero/efectos de los fármacos , Útero/patología , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/biosíntesis , Receptor beta de Estrógeno/metabolismo , Femenino , Inmunohistoquímica , Hibridación Fluorescente in Situ , Microscopía Inmunoelectrónica , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , Células del Estroma/patología , Útero/metabolismoRESUMEN
The action of interleukin-6 (IL-6) impacts female reproduction. Although IL-6 was recently shown to inhibit cilia activity in human fallopian tubes in vitro, the molecular mechanisms underlying IL-6 signaling to tubal function remain elusive. Here, we investigate the cellular localization, regulation, and possible function of two IL-6 receptors (IL-6R alpha and gp130) in mouse and human fallopian tubes in vivo. We show that IL-6R alpha is restricted to the cilia of epithelial cells in both mouse and human fallopian tubes. Exogenous 17beta-estradiol (E(2)), but not progesterone (P(4)), causes a time-dependent decrease in IL-6R alpha expression, which is blocked by the estrogen receptor (ER) antagonist ICI-182,780. Exposure of different ER-selective agonists propyl-(1H)-pyrazole-1,3,5-triyl-trisphenol or 2,3-bis-(4-hydroxyphenyl)-propionitrile demonstrated an ER subtype-specific regulation of IL-6R alpha in mouse fallopian tubes. In contrast to IL-6R alpha, gp130 was detected in tubal epithelial cells in mice but not in humans. In humans, gp130 was found in the muscle cells and was decreased in the periovulatory and luteal phases during the reproductive cycles, indicating a species-specific expression and regulation of gp130 in the fallopian tube. Expression of tubal IL-6R alpha and gp130 in IL-6 knockout mice was found to be normal; however, E(2) treatment increased IL-6R alpha, but not gp130, in IL-6 knockout mice when compared with wild-type mice. Furthermore, expression levels of IL-6R alpha, but not gp130, decreased in parallel with estrogenic accelerated oocyte-cumulus complex (OCC) transport in mouse fallopian tubes. Our findings open the possibility that cilia-specific IL-6R alpha may play a role in the regulation of OCC transport and suggest an estrogen-regulatory pathway of IL-6R alpha in the fallopian tube.