Effect of estrogen on the blood supply of pituitary autografts in rats.

Estrogens are known to cause pituitary enlargement and lactotroph proliferation. They also modulate pituitary angiogenesis and induce tumor formation. Pituitary grafts, due to the loss of hypothalamic dopamine, also show lactotroph hyperplasia. We investigated the role of estrogen on rat pituitary autograft vascularization by light and transmission electron microscopy, and assessed prolactin (PRL) blood levels, microvessel density (MVD) and cell proliferation using the BrdU labeling index. All adenohypophysial cell types were identified by immunohistochemistry (streptavidin-biotin-peroxidase complex method). The proangiogenic factors, vascular endothelial growth factor (VEGF), its receptor Flk-1, and hypoxia inducible factor-1alpha (HIF-1alpha) were similarly demonstrated. The prevalence of lactotrophs, as well as more intense staining for VEGF, Flk-1 and HIF-1alpha, was noted in those grafts exposed to estrogen, mainly in the area surrounding the central necrotic core. Immunostaining showed Flk-1 expression increased in endothelial cells of the estrogen-exposed grafts as compared with those unexposed. In contrast to the grafts not exposed to estrogen, in the estrogen-exposed grafts, only fenestrated endothelium could be demonstrated, suggesting that estrogen induces fenestration of newly formed capillaries. There was an increase in blood PRL levels in the estrogen-treated groups as compared with controls. Both MVD and BrdU labeling indices were higher in grafts exposed to estrogen, especially after 4 weeks. Our results suggest that estrogen administration not only enhances the expression of proangiogenic factors in the pituitary grafts but also induces their expression at earlier stages, leading to rapid neoformation of purely fenestrated capillaries.