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 (E2) pellets in female mice and studied them for 2.5 months. Pituitary weight in female mice increased 2-fold after E2 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 E2 administration, and lactotroph hyperplasia was also observed. Pregnancy induced pituitary cell cycle proliferative and inhibitory responses at the G1/S checkpoint. Differential cell cycle regulator expression included cyclin-dependent kinase inhibitors, p21 Cip1, p27Kip1, and cyclin D1. Pituitary cell cycle responses to E2 administration partially recapitulated those effects observed at mid-late pregnancy, coincident with elevated circulating mouse E2, including increased expression of proliferating cell nuclear antigen, Ki-67, p15INK4b, and p21Cip1. Nuclear localization of pituitary p21Cip1 was demonstrated at mid-late pregnancy but not during E2 administration, suggesting a cell cycle inhibitory role for p21Cip1 in pregnancy, yet a possible proproliferative role during E2administration. 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. Copyright © 2012 by The Endocrine Society.