Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice

Sylvia L. Asa, Michele A. Kelly, David Grandy, Malcolm J. Low

    Research output: Contribution to journalArticle

    130 Citations (Scopus)

    Abstract

    Tuberoinfundibular dopamine tonically inhibits PRL expression and secretion from the pituitary gland by the activation of dopamine D2 receptors (D2R) localized on lactotrophs. Mutant female mice that lack D2Rs have persistent hyperprolactinemia but also develop extensive hyperplasia of pituitary lactotrophs and peliosis of the adenohypophysis at 9 to 12 months of age, while age-matched male D2R-deficient mice have no morphologic adenohypophysial lesion. We now report that both female and male D2R-deficient mice 17 to 20 months of age develop pituitary lactotroph adenomas. Of 12 aged female mice examined, all developed monohormonal PRL-immunoreactive neoplasms that had a characteristic juxtanuclear Golgi pattern of PRL staining and loss of the reticulin fiber network. Several of these adenomas were 50-fold larger than normal glands with marked suprasellar extension and invasion of brain but no gross evidence of distant metastases. They also had striking peliosis that was more marked than the lesion seen in the hyperplastic pituitaries of the younger females. These findings demonstrate that a chronic loss of neurohormonal dopamine inhibition promotes the hyperplasia-neoplasia sequence in adenohypophysial lactotrophs. Our results are analogous to previous data indicating that protracted stimulation of adenohypophysial cells by hormones or growth factors results in proliferation with initial hyperplasia followed by the development of neoplasia. Six aged male D2R-deficient mice had slightly enlarged anterior pituitaries similar in size to normal female glands. However, each case exhibited multifocal, microscopic lactotroph adenomas with strong nuclear immunoreactivity for estrogen receptors and Pit-1 transcription factor. The unexpected development of adenomas in males without preexisting or concomitant hyperplasia suggests that prolonged loss of dopamine inhibition may also cause neoplasia by distinct cellular mechanisms in male and female animals.

    Original languageEnglish (US)
    Pages (from-to)5348-5355
    Number of pages8
    JournalEndocrinology
    Volume140
    Issue number11
    StatePublished - 1999

    Fingerprint

    Lactotrophs
    Prolactinoma
    Pituitary Neoplasms
    Hyperplasia
    Dopamine
    Purpura
    Adenoma
    Neoplasms
    Anterior Pituitary Hormones
    Reticulin
    Hyperprolactinemia
    Anterior Pituitary Gland
    Dopamine D2 Receptors
    Estrogen Receptor alpha
    Pituitary Gland
    mouse DRD2 protein
    Intercellular Signaling Peptides and Proteins
    Transcription Factors
    Staining and Labeling
    Neoplasm Metastasis

    ASJC Scopus subject areas

    • Endocrinology
    • Endocrinology, Diabetes and Metabolism

    Cite this

    Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice. / Asa, Sylvia L.; Kelly, Michele A.; Grandy, David; Low, Malcolm J.

    In: Endocrinology, Vol. 140, No. 11, 1999, p. 5348-5355.

    Research output: Contribution to journalArticle

    Asa, Sylvia L. ; Kelly, Michele A. ; Grandy, David ; Low, Malcolm J. / Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice. In: Endocrinology. 1999 ; Vol. 140, No. 11. pp. 5348-5355.
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