The majority of pituitary adenomas in humans are nonmetastasizing, monoclonal neoplasms that occur in approximately 20% of the general population. Their development has been linked to a combination of extrinsic factors and intrinsic defects. We now demonstrate with transgenic mice that targeted and chronic overexpression of LH causes ovarian hyperstimulation and subsequent hyperproliferation of Pit-1-positive cells that culminates in the appearance of functional pituitary adenomas ranging from focal to multifocal expansion of lactotropes, somatotropes, and thyrotropes. Tumors fail to develop in ovariectomized mice, indicating that contributions from the ovary are necessary for adenoma development. Although the link between chronic ovarian hyperstimulation and PRL-secreting adenomas was expected, the involvement of somatotropes and thyrotropes was surprising and suggests that multiple ovarian hormones may contribute to this unusual pathological consequence. In support of this idea, we have found that ovariectomy followed by estrogen replacement results in the expansion of lactotropes selectively in LH overexpressing mice, but not somatotropes and thyrotropes. Collectively, these data indicate that estrogen is sufficient for the formation of lactotrope adenomas only in animals with a hyperstimulated ovary, whereas the appearance of GH- and TSH-secreting adenomas depends on multiple ovarian hormones. Together, our data expand current models of pituitary tumorigenesis by suggesting that chronic ovarian hyperstimulation may underlie the formation of a subset of pituitary adenomas containing lactotropes, somatotropes, and thyrotropes.
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