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.