RESUMO
Mice homozygous for the targeted disruption of the glycoprotein hormone alpha-subunit (alphaGsu) display hypertrophy and hyperplasia of the anterior pituitary thyrotropes. Thyrotrope hyperplasia results in tumors in aged alphaGsu(-/-) mice. These adenomatous pituitaries can grow independently as intrascapular transplants in hypothyroid mice, suggesting that they have progressed beyond simple hyperplasia. We used magnetic resonance imaging to follow the growth and regression of thyrotrope adenomatous hyperplasia in response to thyroid hormone treatment and discovered that the tumors retain thyroid hormone responsiveness. Somatostatin (SMST) and its diverse receptors have been implicated in cell proliferation and tumorigenesis. To test the involvement of SMST receptor 2 (SMSTR2) in pituitary tumor progression and thyroid hormone responsiveness in alphaGsu(-/-) mutants, we generated Smstr2(-/-), alphaGsu(-/-) mice. Smstr2(-/-), alphaGsu(-/-) mice develop hyperplasia of thyrotropes, similar to alphaGsu(-/-) mutants, demonstrating that SMSTR2 is dispensable for the development of pituitary adenomatous hyperplasia. Thyrotrope hyperplasia in Smstr2(-/-), alphaGsu(-/-) mice regresses in response to T4 treatment, suggesting that SMSTR2 is not required in the T4 feedback loop regulating TSH secretion.
Assuntos
Neoplasias Hipofisárias/patologia , Receptores de Somatostatina/fisiologia , Tiroxina/farmacologia , Animais , Northern Blotting , Feminino , Subunidade alfa de Hormônios Glicoproteicos/genética , Subunidade alfa de Hormônios Glicoproteicos/fisiologia , Hiperplasia/patologia , Hipotireoidismo/patologia , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Hipofisárias/genética , RNA/química , RNA/isolamento & purificação , Receptores de Somatostatina/genéticaRESUMO
Mice homozygous for a disruption in the alpha-subunit essential for TSH, LH, and FSH activity (alphaGsu-/-) exhibit hypothyroidism and hypogonadism similar to that observed in TSH receptor-deficient hypothyroid mice (hyt) and GnRH-deficient hypogonadal mutants (hpg). Although the five major hormone-producing cells of the anterior pituitary are present in alphaGsu-/- mice, the relative proportions of each cell type are altered dramatically. Thyrotropes exhibit hypertrophy and hyperplasia, and somatotropes and lactotropes are underrepresented. The size and number of gonadotropes in alphaGsu mutants are not remarkable in contrast to the hypertrophy characteristic of gonadectomized animals. The reduction in lactotropes is more severe in alphaGsu mutants (13-fold relative to wild-type) than in hyt or hpg mutants (4.5- and 1.5-fold, respectively). In addition, T4 replacement therapy of alphaGsu mutants restores lactotropes to near-normal levels, illustrating the importance of T4, but not alpha-subunit, for lactotrope proliferation and function. T4 replacement is permissive for gonadotrope hypertrophy in alphaGsu mutants, consistent with the role for T4 in the function of gonadotropes. This study reveals the importance of thyroid hormone in developing the appropriate proportions of anterior pituitary cell types.
Assuntos
Subunidade alfa de Hormônios Glicoproteicos/genética , Hormônio do Crescimento/biossíntese , Mutagênese , Adeno-Hipófise/patologia , Prolactina/biossíntese , Tiroxina/fisiologia , Animais , Contagem de Células , Divisão Celular , Nanismo/prevenção & controle , Hiperplasia , Hipogonadismo/genética , Hipogonadismo/patologia , Hipotireoidismo/genética , Hipotireoidismo/patologia , Imuno-Histoquímica , Camundongos , Camundongos Mutantes , Adeno-Hipófise/metabolismo , Tireotropina/deficiência , Tireotropina/genética , Tiroxina/farmacologia , Tiroxina/uso terapêuticoRESUMO
Pigmented rabbits were pretreated for 3 days with dexamethasone (0.4 mg/kg) or indomethacin (6 mg/kg tid) and then, along with control rabbits, treated with cryopexy administered to the peripheral retina. Drug treatment was continued for the duration of the study. Vitreous fluorophotometry (VFP) was performed prior to cryopexy and on postcryopexy days 3 and 7. Breakdown of the blood-retinal barrier occurred in all three groups but was significantly greater in the control group. Differences were most marked on postcryopexy day 7 when intravitreous fluorescein leakage was decreased to 36% of control in dexamethasone-treated rabbits and 42% of the control group in indomethacin-treated rabbits. Some rabbits, after dexamethasone or indomethacin treatment for 3 days, were given a single posterior cryoapplication just inferior to the optic nerve. On postcryopexy days 1, 3, 7, and 10, VFP was performed by scanning over the treated area. In control rabbits, fluorescein leakage increased over 3 days, while in dexamethasone- and indomethacin-treated rabbits, this increase was significantly blunted. These data demonstrate the beneficial effects of dexamethasone and indomethacin on cryopexy-induced breakdown of the blood-retinal barrier and also suggest a possible mechanism for how such a breakdown occurs.
