Pituitary Tumorigenesis in Prolactin Gene-Disrupted Mice

Abstract

Targeted disruption [knockout (KO)] of the mouse prolactin (PRL) gene created an animal model of primary isolated PRL deficiency in which there is no detectable PRL bioactivity. Pituitary glands of young adult female PRLKO mice were hyperplastic, and many cells had expanded cytoplasms with granular accumulations of an N-terminal peptide encoded by the disrupted PRL gene (KO/10 peptide). Confocal imaging showed that the pituitaries in PRL(+/+) and PRL(+/-) females contained dense accumulations of apparently Golgi-associated immunoreactive PRL. PRLKO female mice (15-18 months old) developed hyperemic pituitary adenomas. The pituitary tumors in PRLKO mice synthesized the KO/10 peptide, which implies that the tumors arise from the lactotroph lineage. Anchorage-independent growth was observed among pituitary cells from PRLKO mice, aged 8 months or older, but not in cells from 3-month-old PRLKO mice. GH cells appeared to be normal in PRLKO pituitaries, but were displaced by the hyperplastic and hypertrophic growth of KO/10-positive cells. Bromocriptine suppressed mean pituitary weight in 8-month-old PRLKO mice compared with vehicle-treated PRLKO animals (20 +/- 0.01 and 60 +/- 10 mg; P < 0.01). We infer that pituitary lactotrophs of PRLKO mice suffer from a dual pathology that includes hypertrophy resulting from endoplasmic reticulum expansion and hyperplasia, with adenomatous transformation, in part as a consequence of disrupted dopaminergic feedback regulation.

Collision lesions of the sella: co-existence of craniopharyngioma with gonadotroph adenoma and of Rathke’s cleft cyst with corticotroph adenoma

“…Loss of the inhibitory effect of hypothalamic dopamine release due to tumoral ''stalk section effect'' was suggested as a likely etiology [15]. Investigations on transgenic mice [40] confirm the existence of this mechanism. The association of lactotroph hyperplasia and prolactinoma is known to occur in humans as well [41].…”

Genesis of Prolactinomas: Studies Using Estrogen-Treated Animals

“…Also, their actions on the lactotropes in the presence of pituitary mesenchymal variant folliculo-stellate cells have not been tested. Additionally, overexpression of many of these factors using a transgenic approach have resulted only in hyperplasia, and they resulted in adenoma formation only in old age and/or only in females, suggesting that endogenous estrogens are a requirement [59][60][61]. Therefore, the role of these growth factors in the mechanisms leading to tumorigenesis could not be critically evaluated.…”

Use of Prolactin Receptor Antagonist to Better Understand Prolactin Regulation of Pituitary Homeostasis

“…Since D2R KO mice develop hyperprolactinemia, pituitary hyperplasia and, finally, pituitary adenomas, it was suggested that both the lack of dopamine inhibition and stimulation of cell proliferation induced by high circulating levels of PRL were responsible for the anterior pituitary cell growth observed in these mice [79]. However, it was later observed that PRL KO [80] and PRLR KO [81] mice also exhibited anterior pituitary hyperplasia. It was concluded that activation of PRLR signaling was not involved in promoting pituitary adenoma formation.…”