Genetic disruption of dopamine production results in pituitary adenomas and severe prolactinemia

Authors: HNASKO, THOMAS - UNIVERSITY OF WASHINGTON; Hnasko, Robert; SOTAK, BETHANY - UNIVERSITY OF WASHINGTON; KAPUR, RAJ - UNIVERSITY OF WASHINGTON

Submitted to: Neuroendocrinology Journal
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/7/2007
Publication Date: 7/4/2007
Citation: Hnasko, T.S., Hnasko, R.M., Sotak, B.N., Kapur, R.P. 2007. Genetic disruption of dopamine production results in pituitary adenomas and severe prolactinemia. Neuroendocrinology Journal. 86(1): 48-57

Interpretive Summary: Prolactinomas are the most common type of pituitary tumor. These tumors arise from the cellular expansion of the prolactin producing lactotrophs located in the pituitary gland. Growth of these tumors results in blood hyper-prolactinemia, a status that is primarily associated with lactation. The pituitary is in close proximity to the brain and excessive growth can have a negative impact on the visual system and other fundamental brain functions. Clinically, prolactinomas are managed by either invasive surgery or pharmacological use of dopamine receptor antagonists. The latter has the effect of both suppressing the overproduction of prolactin and shrinking the tumors. Much indirect evidence has accumulated to demonstrate that the neurotransmitter dopamine acts directly on pituitary lactotrophs to suppress prolactin production and cell growth. In this report we use a molecular genetic approach to demonstrate for the first time that the direct loss of dopamine in the specific brain region call the hypothalamus results in the formation of prolactinomas. These data unequivocally demonstrate that brain derived dopamine serves as the chronic negative regulator of pituitary lactoroph growth and prolactin production.

Technical Abstract: Dopamine release from tuberoinfundibular dopamine neurons into the median eminence activates dopamine-D2 receptors in the pituitary gland where it inhibits lactotroph function. We have previously described genetic dopamine-deficient mouse models which lack the ability to synthesize dopamine. Because these animals require daily treatment with 3,4 L-dihydroxyphenylalanine (L-dopa) to survive, it has not been possible to examine the consequences of chronic loss of dopamine on pituitary physiology. Here, we use viral-mediated gene transfer to selectively restore dopamine to the dorsal striatum of dopamine-deficient mice which allows the mice to survive without L-dopa. We find that mice chronically lacking tuberoinfundibular dopamine secrete large amounts of prolactin due to the development of severely enlarged pituitaries composed principally of hyperplastic hypertrophic lactotrophs and which include focal prolactinomas. In addition, these mice have elevated serum growth hormone levels and aged males develop hypertrophy of the seminal vesicles. These results are consistent with the hypothesis that hypothalamic dopamine is a critical inhibitor of lactotroph proliferation and suggest additional roles for dopamine in the regulation of pituitary function.