VEGF expression has been described in all cell types in the normal pituitary, with greater expression in somatotroph and follicle-stellate cells. Using immunohistochemistry higher VEGF expression has been shown in the normal gland compared with adenomas (Lloyd et al. 1999), while the opposite has also been published. In a group of pituitary adenomas, ACTH and GH secreting adenomas, pituitary carcinomas had the strongest VEGF immunoreactivity (Lloyd et al. 1999). On the other hand, Viacava et al. (2003) found no differences in VEGF expression among tumors of different histotype, and McCabe et al. (2002) comparing VEGF in a series of adenomas composed of 77 % non functioning adenomas, and only 4 % of prolactinomas, found highest expression in nonfunctioning adenomas and GH producing adenomas. Elevated serum VEGF concentrations have been demonstrated in patients harboring pituitary tumors, and approximately 90 % of human pituitary tumors cultured in vitro show measurable VEGF secretion.

Using Western blot analysis of pituitary adenomas we found that VEGF protein expression was higher in prolactinomas compared to nonfunctioning (NF), GH, and ACTH secreting adenomas (Cristina et al. 2010). This finding may be related to the high percentage of macroprolactinomas in the series studied (11/12). In this respect, using angiogenic markers, it has been described that macroprolactinomas are significantly more vascularized than microprolactinomas. Furthermore, lower VEGF found in ACTH-producing adenomas may be consistent with the finding that VEGF production can be suppressed by glucocorticoids which are potent inhibitors of VEGF production in vitro (Lohrer et al. 2001). On the other hand, pituitary adenoma VEGF expression was similar in both sexes and was not influenced by age or years of adenoma evolution, when all adenomas were considered. This is in agreement with most studies which reveal that sex, age or even rate of recurrence did not influence VEGF expression in pituitary tumors.

These data indicate that even though the role of angiogenesis in pituitary adenomas is contentious, VEGF might contribute to adequate temporal vascular supply with mechanisms other than endothelial cell proliferation. Tumor angiogenesis in the pituitary, as well as in other endocrine neoplasms, probably reflects the basic observation that tumors require neovascularization to grow; however, the changes that occur may be somewhat different from some other tissues that are less highly vascularized in the nonneoplastic state. Some data suggest that VEGF may prolong cell survival by inducing expression of the anti-apoptotic protein bcl-2 in pituitary adenomas, suggesting that part of its angiogenic activity is related to protection of endothelial cells from apoptosis. VEGF has been associated to intratumoral hemorrhage (Arita et al. 2004), and might also participate in the occurrence of pituitary peliosis, a form of vasculogenic mimicry. Peliosis may be linked to the permeabilizing function of this growth factor, and to the increased fenestration induced in blood vessels stimulated by VEGF overexpression. Peliosis occurrence has been related to high VEGF expression in hepatocarcinogenesis, spleen damage, and in a lethal hepatic syndrome in mice. This process may be seen in prolactinomas and other pitutitary adenomas, though it usually goes unrecognized. In dopamine D2 receptor knockout (Drd2 ^−/− ) mice which develop lactotroph hyperplasia and eventually prolactinomas, we have described increased peliosis occurrence in these pituitary tumors in association with increased VEGF expression (Cristina et al. 2005).

FGF2 participates in pituitary development and proliferation and regulates hormone synthesis and secretion, affecting prolactin and TSH production. It is mainly produced by folliculostellate cells (FS) (Ferrara et al. 1987), although somatotrophs and gonadotrophs have also been reported to be sources of this growth factor. FGF2 participates in estradiol-mediated prolactinoma induction in rats under both physiological and pharmacological conditions. In the hyperplastic pituitaries of Drd2 ^−/− mice, it induces prolactin secretion and cellular proliferation, and, interestingly has a differential subcellular distribution compared to that of wildtype pituitaries, which could be associated with different biological roles of this angiogenic factor in both genotypes (Cristina et al. 2007a). FGF2 is also expressed by human pituitary adenoma cells in vitro, and high levels of serum FGF2 were found in patients bearing pituitary tumors, declining following surgical adenomectomy. In the case of a giant invasive prolactinoma with loss of response to dopamine agonist therapy we have recently reported strong immunoreactivity for both angiogenic factors VEGF and FGF2, as well as immunoreactivity for the endothelial cell marker CD31 indicating high vascularization of the adenoma (Mallea-Gil et al. 2009).