RESUMO
This study investigated the effect of hCG or GnRH on structural changes of the corpora lutea (CL) and the regulation of the expression of steroidogenic enzymes involved in P4 secretion in post-ovulatory (po-CL) and accessory CL (acc-CL). Sixty-four ewes were assigned to three groups receiving: 300 IU of hCG (hCG) or 4⯵g Buserelin (GnRH) or 1â¯mL of saline solution (Control) on Day (d) 4 post artificial insemination (FTAI). Laparoscopic ovarian were performed on d 4, 14 and, 21 post-FTAI to determine the numbers of CL. Blood samples were collected for serum LH and P4 analysis. On d 14 post-FTAI, both CL were removed from the ovary to determine large luteal cell (LLC) number and to evaluate the expression of steroidogenic enzymes (HSD3B1, STAR, CYP11A1). Only hCG and GnRH treated ewes generated acc-CL. The LLC in both po- and acc-CL were significantly greater in the hCG group compared to GnRH and Control groups (P<0.05). Overall, hCG group showed the greatest immunodetection of HSD3B1and STAR in both po- and acc-CL (P<0.05). rnRNA expression of HSD3B1, STAR and CYP11A1 in the acc-CL tended to be greater in hCG group than in GnRH group (P<0.1). The LH concentration was increased in GnRH group (P<0.05) and P4 concentration was greater in hCG group compared to the other groups (P<0.05). In conclusion, administration of hCG has a notably impact on acc-CL development and the expression of steroidogenic enzymes compared to GnRH treatment in ewes. This leads to elevated P4 concentration and improved luteal function.
Assuntos
Gonadotropina Coriônica , Corpo Lúteo , Hormônio Liberador de Gonadotropina , Fase Luteal , Progesterona , Animais , Feminino , Ovinos/fisiologia , Corpo Lúteo/efeitos dos fármacos , Corpo Lúteo/metabolismo , Progesterona/sangue , Progesterona/metabolismo , Gonadotropina Coriônica/farmacologia , Gonadotropina Coriônica/administração & dosagem , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Liberador de Gonadotropina/metabolismo , Fase Luteal/efeitos dos fármacos , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Hormônio Luteinizante/metabolismo , FosfoproteínasRESUMO
[This corrects the article DOI: 10.1155/2014/608497.].
RESUMO
Preclinical and clinical studies support that Notch signaling may play an important oncogenic role in cancer, but there is scarce information for pituitary tumors. We therefore undertook a functional study to evaluate Notch participation in pituitary adenoma growth. Tumors generated in Nude mice by subcutaneous GH3 somatolactotrope cell injection were treated in vivo with DAPT, a γ-secretase inhibitor, thus inactivating Notch signaling. This treatment led to pituitary tumor reduction, lower prolactin and GH tumor content and a decrease in angiogenesis. Furthermore, in silico transcriptomic and epigenomic analyses uncovered several tumor suppressor genes related to Notch signaling in pituitary tissue, namely Btg2, Nr4a1, Men1, Zfp36 and Cnot1. Gene evaluation suggested that Btg2, Nr4a1 and Cnot1 may be possible players in GH3 xenograft growth. Btg2 mRNA expression was lower in GH3 tumors compared to the parental line, and DAPT increased its expression levels in the tumor in parallel with the inhibition of its volume. Cnot1 mRNA levels were also increased in the pituitary xenografts by DAPT treatment. And the Nr4a1 gene was lower in tumors compared to the parental line, though not modified by DAPT. Finally, because DAPT in vivo may also be acting on tumor microenvironment, we determined the direct effect of DAPT on GH3 cells in vitro. We found that DAPT decreases the proliferative, secretory and migration potential of GH3 cells. These results position selective interruption of Notch signaling as a potential therapeutic tool in adjuvant treatments for aggressive or resistant pituitary tumors.
Assuntos
Adenoma/patologia , Neoplasias Hipofisárias/patologia , Receptores Notch/antagonistas & inibidores , Adenoma/metabolismo , Animais , Linhagem Celular Tumoral , Diaminas/farmacologia , Feminino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Hipofisárias/metabolismo , Prolactina/metabolismo , Ratos , Receptores Notch/metabolismo , Transdução de Sinais , Tiazóis/farmacologia , Carga TumoralRESUMO
The role of angiogenesis in pituitary tumor development has been questioned, as pituitary tumors have been usually found to be less vascularized than the normal pituitary tissue. Nevertheless, a significantly higher degree of vasculature has been shown in invasive or macropituitary prolactinomas when compared to noninvasive and microprolactinomas. Many growth factors and their receptors are involved in pituitary tumor development. For example, VEGF, FGF-2, FGFR1, and PTTG, which give a particular vascular phenotype, are modified in human and experimental pituitary adenomas of different histotypes. In particular, vascular endothelial growth factor, VEGF, the central mediator of angiogenesis in endocrine glands, was encountered in experimental and human pituitary tumors at different levels of expression and, in particular, was higher in dopamine agonist resistant prolactinomas. Furthermore, several anti-VEGF techniques lowered tumor burden in human and experimental pituitary adenomas. Therefore, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF, making permeable pituitary endothelia, might contribute to adequate temporal vascular supply and mechanisms other than endothelial cell proliferation. The study of angiogenic factor expression in aggressive prolactinomas with resistance to dopamine agonists will yield important data in the search of therapeutical alternatives.
RESUMO
La rata hembra resulta un interesante modelo experimental para estudiar el desarrollo del control de las hormonas hipofisarias involucradas en la reproducción. Desde el nacimiento hasta la eclosión puberal transcurren aproximadamente 36 días que pueden ser divididos en 4 etapas: a) neonatal, hasta el día 7 de vida, b) infantil, de 7 a 21, c) juvenil, 21 a 30 días, y d) peripuberal, período que culmina con la primera ovulación. Durante estas etapas los perfiles hormonales son definidos y sujetos a un control característico para cada período. La prolactina está baja hasta el fin del período infantil, momento en que comienza a aumentar gradualmente. Este aumento está relacionado con una maduración de mecanismos liberadores de la prolactina (como el sistema serotoninérgico y el estradiol), en presencia de un aumento del tono dopaminérgico inhibitorio. La prolactina en aumento produce una maduración de los receptores ováricos a LH, y una desensibilización de receptores dopaminérgicos, ambos eventos importantes para la eclosión puberal. La FSH aumenta desde el nacimiento hasta alcanzar el día 12 de vida valores máximos. Luego desciende permaneciendo baja hasta la pubertad. Las causas de este perfil de secreción son múltiples: a los 12 días de edad hay una aumentada sensibilidad de la hipófisis a la LHRH, y una mayor liberación de FSH por serotonina. Por otro lado, frente a una escasa retroalimentación negativa estrogénica y bajos niveles de inhibina, la FSH está bajo control negativo de la...