title: Estradiol partially recapitulates murine pituitary cell cycle response to pregnancy.
abstract: Because pregnancy and estrogens both induce pituitary lactotroph hyperplasia, we assessed the expression of pituitary cell cycle regulators in two models of murine pituitary hyperplasia. Female mice were assessed during nonpregnancy, pregnancy, day of delivery, and postpartum. We also implanted estradiol (E(2)) pellets in female mice and studied them for 2.5 months. Pituitary weight in female mice increased 2-fold after E(2) administration and 1.4-fold at day of delivery, compared with placebo-treated or nonpregnant females. Pituitary proliferation, as assessed by proliferating cell nuclear antigen and/or Ki-67 staining, increased dramatically during both mid-late pregnancy and E(2) administration, and lactotroph hyperplasia was also observed. Pregnancy induced pituitary cell cycle proliferative and inhibitory responses at the G(1)/S checkpoint. Differential cell cycle regulator expression included cyclin-dependent kinase inhibitors, p21(Cip1), p27(Kip1), and cyclin D1. Pituitary cell cycle responses to E(2) administration partially recapitulated those effects observed at mid-late pregnancy, coincident with elevated circulating mouse E(2), including increased expression of proliferating cell nuclear antigen, Ki-67, p15(INK4b), and p21(Cip1). Nuclear localization of pituitary p21(Cip1) was demonstrated at mid-late pregnancy but not during E(2) administration, suggesting a cell cycle inhibitory role for p21(Cip1) in pregnancy, yet a possible proproliferative role during E(2) administration. Most observed cell cycle protein alterations were reversed postpartum. Murine pituitary meets the demand for prolactin during lactation associated with induction of both cell proliferative and inhibitory pathways, mediated, at least partially, by estradiol.
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. melmed@csmc.edu
authors.forename: Yoel
authors.initials: Y
authors.lastname: Toledano
authors.forename: Svetlana
authors.initials: S
authors.lastname: Zonis
authors.forename: Song-Guang
authors.initials: SG
authors.lastname: Ren
authors.forename: Kolja
authors.initials: K
authors.lastname: Wawrowsky
authors.forename: Vera
authors.initials: V
authors.lastname: Chesnokova
authors.forename: Shlomo
authors.initials: S
authors.lastname: Melmed
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D002455:Cell Division / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D019394:Ki-67 Antigen; D019938:Cyclin D1; D004958:Estradiol