Changes of tyrosine phosphorylation in liver and kidney of polycystic ovarian rats induced by letrozole / Cambios de fosforilación de tirosina en hígado y riñón de ratas ováricas poliquísticas inducidas por letrozol

Letrozole (Letro) is a drug commonly used for breast cancer treatment since it can decrease estrogen level. In experimental animal, the Letro has been used to induce the polycystic ovarian syndrome (PCOS) model. Tyrosine phosphorylation (TyrPho) is an essential process in various biological functions both normal and abnormal conditions especially reproduction. Although some side effects of Letro are reported, the alterations of TyrPho responsible for liver and kidney functions have never been demonstrated. In this study, the blood serum, liver, and kidney of control and PCOS rats induced with Letro (orally, 1 mg/ KgBW) for consecutive 21 days were used to determine the serum biochemical components and to investigate the TyrPho expression using western blot analysis. Histopathology of such tissues was observed by Masson's trichrome staining. The results showed that Letro did not affect histological structures but significantly increased the serum levels of urea nitrogen, cholesterol, triglyceride, HDL, LDL, ALT, AST, and alkaline phosphatase. Additionally, the TyrPho protein expressions of 32 and 27 kDas in liver and of 55 and 43 kDas in kidney were increased while of a kidney 26 kDa was decreased as compared to those of control. In conclusion, this recent study indicated that the changes of TyrPho proteins in liver and kidney induced with Letro associated with their functions by alteration of serum biochemical levels.

El letrozol (Letro) es un medicamento utilizado comúnmente para el tratamiento del cáncer de mama, debido a que puede disminuir el nivel de estrógeno. En animales de experimentación, el Letro se ha utilizado para inducir el modelo de síndrome de ovario poliquístico (PCOS). La fosforilación de tirosina (TyrPho) es un proceso esencial en diversas funciones biológicas, tanto en condiciones normales como anormales, especialmente en la reproducción. A pesar de informes que indican algunos efectos secundarios de Letro, no se han demostrado las alteraciones de TyrPho responsables de las funciones hepáticas y renales. En este estudio, el suero sanguíneo, el hígado y el riñón control y las ratas PCOS inducidas con Letro (por vía oral, 1 mg / KgBW) durante 21 días consecutivos se usaron para determinar los componentes bioquímicos del suero y para investigar la expresión de TyrPho usando análisis de transferencia Western. La histopatología de los tejidos se observó mediante la tinción tricrómica de Masson. Los resultados mostraron que Letro no afectó las estructuras histológicas, pero aumentó significativamente los niveles séricos de urea, colesterol, triglicéridos, HDL, LDL, ALT, AST y fosfatasa alcalina. Además, las expresiones de la proteína TyrPho de 32 y 27 kDas en el hígado y de 55 y 43 kDas en el riñón aumentaron mientras que en un riñón disminuyeron 26 kDa en comparación con el control. En conclusión, este estudio indicó que los cambios de las proteínas TyrPho en el hígado y los riñones inducidos con Letro se asociaron con sus funciones mediante la alteración de los niveles bioquímicos en suero.

Novel mechanisms underlying anti-polycystic ovary like syndrome effects of electroacupuncture in rats: suppressing SREBP1 to mitigate insulin resistance, mitochondrial dysfunction and oxidative stress

BACKGROUND: Acupuncture, a therapy of traditional Chinese medicine, is confirmed to exert the therapeutic action on polycystic ovary syndrome (PCOS). However, the detailed therapeutic mechanisms of acupuncture in PCOS remain ambiguous. In this study, we further investigated whether electroacupuncture (EA) alleviated PCOS-like symptoms in rats via regulating a metabolic regulator, sterol regulatory element binding protein-1 (SREBP1). Methods: The PCOS-like rat model was built by hypodermic injection with dehydroepiandrosterone (DHEA). The rats were subjected to EA intervention (ST29 and SP6 acupuncture points) for 5 weeks. Primary granulosa cells were isolated from control and PCOS-like rats for evaluating insulin resistance, mitochondrial dysfunction and oxidative stress in vitro. RESULTS: The expression of SREBP1 was increased in PCOS-like rats, which was suppressed by EA treatment. In addition, lentivirus-mediated overexpression of SREBP1 restrained EA treatment-induced improvement in pathological changes, serum hormone levels and insulin resistance in rats. In addition, overexpression of SREBP1 repressed insulin-stimulated phosphorylation of insulin receptor ß (IR) and AKT in primary granulosa cells. Moreover, upregulation of SREBP1 further exacerbated mitochondrial dysfunction and oxidative stress in granulosa cells isolated from PCOS-like rats. Mechanically, EA treatment suppressed SREBP1 expression through inducing the activation of AMP-activated protein kinase (AMPK) signaling pathway in PCOS-like rats. CONCLUSION: EA intervention alleviated PCOS-like symptoms in rats via improving IR, mitochondrial dysfunction and oxidative stress through regulating SREBP1, a lipid metabolism regulator. Our findings illuminate the novel protective mechanisms of EA in the treatment of PCOS.

Changes of the uterine tissue in rats with polycystic ovary syndrome induced by estradiol valerate

Background: Polycystic ovary syndrome [PCOS] is one of the most common hormonal disorders that can lead to irregular menstrual cycles and hyperandrogenism. Reduced levels of progesterone and increased estrogen in these women can perpetually stimulate the endometrial tissue of the uterus. In this study, we assess the effect of PCOS induction by estradiol valerate [EV] in a rat model

Materials and Methods: In this experimental study, adult female Wistar rats that weighed approximately 200 g were divided into control, sham, and experimental groups [n=6 per group]. The experimental group received subcutaneous injections of 2 mg EV for induction of PCOS. We confirmed the presence of PCOS in the experimental group rats. Rats from all groups were subsequently killed, after which their uteri were removed and fixed for histological and cytological analyses. The uterine tissue sections were stained with hematoxylin and eosin [H and E] and iron hematoxylin [iron-H]. We examined epithelium height, thickness of the uterus wall, and frequency of the mitotic cells. The data were assessed at alpha=0.05

Results: Uterine tissue findings from the experimental group showed significant increases in the height of the uterus luminal epithelium, the thickness of the uterus wall, and the frequency of eosinophils in the endometrial stroma. We observed an increased frequency of mitotic cells in the experimental group in both luminal and glandular epithelia of the uterus. An increased rate of the glandular epithelium region was noticeable and significant

Conclusion: Induction of PCOS by EV could change the proliferation rate in the endometrial tissue of the uterus

Síndrome de ovario poliquístico, epilepsia y drogas anticonvulsivantes: ¿Estan relacionados? / Polycystic ovary syndrome, epilepsy and anticonvulsant drugs: are they related?

El Síndrome de ovario poliquístico (SOP) es un tema muy controvertido y lo seguirá siendo por los grandes avances en biología molecular que nos ayudan a entender mejor su etiología. Hoy, para definir SOP, nos regimos por lo consensuado en el encuentro de expertos de Rotterdam de 2003, donde se definió este síndrome con dos de los siguientes tres criterios: oligomenorrea/amenorrea, hiperandrogenismo clínico y/o de laboratorio y poliquistosis ovárica por ecografía, excluyendo la hiperplasia suprarrenal congénita (HSC), el hipotiroidismo, prolactinemias y uso de drogas (ácido valproico). La aplicación de la definición y el diagnóstico de SOP son aún más difíciles cuando se da en adolescentes con menos de tres años de edad ginecológica. Con todo este bagaje de conocimientos y dudas, nos enfrentamos además a otra cuestión sobre ciertas patologías o drogas que parecerían asociarse al SOP y que se pueden dar en cualquier momento de la vida, como es la epilepsia en todas sus formas y las drogas anticonvulsivantes que se utilizan par su tratamiento. Hasta el momento, se discutía si el ácido valproico y la carbamazepina estaban relacionados con el SOP, pero con los recientes hallazgos, parecería que la epilepsia tiene una gran importancia en relación con este síndrome. En esta revisión tratamos de aunar los conocimientos en los tres temas: SOP, epilepsia y anticonvulsivantes para intentar esclarecer el abordaje desde lo médico en el manejo de un adolescente que enfrenta esta problemática.

Immunohistochemical analysis and role of secreted frizzled-related protein-4 in polycystic ovary-induced rat

The role of Wnt signaling and its antagonist; secreted Frizzled Related Protein type 4 [sFPR4] was reported in rodent ovarian follicular development. This study examines immunolocalization of sFRP4 in ovaries of polycystic ovary [PCO] rat model and evaluates its role in follicular growth arrest and its premature differentiation. PCO was induced with daily administration of testosterone propionate [TP] for 1 to 4 weeks while normal control rats were injected only with vehicle. The ovaries underwent histological examination, immunohistochemical analysis of sFRP4 and steroidogenic acute regulatory protein [StAR] and apoptosis analysis. Four-week TP treatment significantly increased the primordial follicles, and significantly decreased the preantral and antral follicles compared to one week TP treatment. TP-treated animals had concomittantly, significant increase of sFPR4 immunoexpression in primordial, primary and preantral follicles as compared to one week TP-treated animals and control groups. Furthermore, sFRP4 immunostaining strongly co-localized in apoptotic granulosa cells. Interestingly, increased sFRP4 immunostaining was associated with increased StAR immunoexpression in follicular theca layer and stroma in four weeks TP-treated rats compared to one week TP-treated rats and control groups. Our data showed a highly significant association between sFRP4 expression and apoptosis in ovaries of four week TP-treated animals. Moreover, co-localization of StAR and sFRP4 could suggest that sFRP4 may play a role in premature differentiation of follicles

Response to the gonadotropin releasing hormone agonist leuprolide in immature female sheep androgenized in utero

Similar to women with Polycystic Ovary Syndrome (PCOS), female sheep treated prenatally with testosterone (T-females) are hypergonadotropic, exhibit neuroendocrine defects, multifollicular ovarian morphology, hyperinsulinemia and cycle defects. Hypergonadotropism and multifollicular morphology may in part be due to developmentally regulated increase in pituitary responsiveness to GnRH and may culminate in increased ovarian estradiol production. In this study, we utilized a GnRH agonist, leuprolide, to determine the developmental impact of prenatal testosterone exposure on pituitary-gonadal function and to establish if prenatal exposure produces changes in the reproductive axis similar to those described for women with PCOS. Eight control and eight T-females were injected intravenously with 0.1 mg of leuprolide acetate per kilogram of body weight at 5, 10 and 20 weeks of age. Blood samples were collected by means of an indwelling jugular vein catheter at 0, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 hours after leuprolide. Area under the curve (AUC) of LH response to leuprolide increased progressively between the three ages studied (P<0.05). AUC of LH in T-females was higher than in control females of the same age at 5 and 10 weeks of age (P<0.05), but similar at 20 weeks of age. AUC of estradiol response was lower at 10 but higher at 20 weeks of age in T-females compared to controls of the same age (P<0.05). Our findings suggest that prenatal T treatment alters the pituitary and ovarian responsiveness in a manner comparable to that observed in women with PCOS.

Polycystic ovarian syndrome: temporal characterization of the induction and reversion process in an experimental model

Numerosos modelos experimentais têm sido desenvolvimos para o estudo da síndrome do ovário policístico em ratos. No presente estudo, a síndrome foi inducida por exposição à luz constante. O processo foi avaliado durante sua indução e inclusive durante sua reversão. O ciclo estral foi analisado através de citologia vaginal; parámetros reprodutivos foram avaliados por acasalamento, bem como a morfologia ovariana. Todos animais desenvolveram a síndrome depois de 13 semanas de luz permanente. As características histológicas dos ovários, na semana 15, foram similares àquelas observadas na síndrome do ovário policístico em humanos e outras espécies. Após a regressão da síndrome, não houve diferenta em nenhum dos parámetros reprodutivos avaliados, quando comparados com o grupo controle.