title: Lack of prolactin receptor signaling in mice results in lactotroph proliferation and prolactinomas by dopamine-dependent and -independent mechanisms.
abstract: Hypothalamic dopamine inhibits pituitary prolactin secretion and proliferation of prolactin-producing lactotroph cells by activating lactotroph dopamine D2 receptors (D2Rs). Conversely, prolactin (PRL) stimulates hypothalamic dopamine neurons via PRL receptors (PRLRs) in a short-loop feedback circuit. We used Drd2(-/-) and Prlr(-/-) mutant mice to bypass this feedback and investigate possible dopamine-independent effects of PRL on lactotroph function. The absence of either receptor induced hyperprolactinemia and large prolactinomas in females. Small macroadenomas developed in aged Prlr(-/-) males, but only microscopic adenomas were found in Drd2(-/-) male mice. Pharmacologic studies in Prlr(-/-) mice with D2R agonists and antagonists demonstrated a significant loss of endogenous dopamine tone, i.e., constitutive inhibitory signaling by the D2R, in the pituitary. However, Prlr(-/-) mice exhibited more profound hyperprolactinemia and larger tumors than did age-matched Drd2(-/-) mice, and there were additive effects in compound homozygous mutant male mice. In vitro, PRL treatment markedly inhibited the proliferation of wild-type female and male Drd2(-/-) lactotrophs, but had no effect on female Drd2(-/-) lactotrophs, suggesting a downregulation or desensitization of PRLR in response to chronic hyperprolactinemia. We conclude that PRL inhibits lactotrophs by two distinct mechanisms: (a) indirectly by activation of hypothalamic dopamine neurons and (b) directly within the pituitary in a dopamine-independent fashion.
authors.affiliation: Vollum Institute, Oregon Health & Science University, Portland, Oregon 97201, USA.
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Schuff
authors.forename: Shane T
authors.initials: ST
authors.lastname: Hentges
authors.forename: Michele A
authors.initials: MA
authors.lastname: Kelly
authors.forename: Nadine
authors.initials: N
authors.lastname: Binart
authors.forename: Paul A
authors.initials: PA
authors.lastname: Kelly
authors.forename: P Michael
authors.initials: PM
authors.lastname: Iuvone
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Low
mesh_terms: D000818:Animals; D002455:Cell Division; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D005260:Female; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology*; D010911:Pituitary Neoplasms / Q000209:etiology*; D011388:Prolactin / Q000378:metabolism*; D015175:Prolactinoma / Q000209:etiology*; D012333:RNA, Messenger / Q000032:analysis; D017448:Receptors, Dopamine D2 / Q000502:physiology; D011981:Receptors, Prolactin / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D011981:Receptors, Prolactin; D004295:Dihydroxyphenylalanine; D011388:Prolactin; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine