Effect of ovariectomy on the proliferative capacity of intrahepatic rat cholangiocytes

Background & Aims: We evaluated the effects of ovariectomy (OVX) and estrogen replacement treatment on cholangiocyte proliferation induced by bile duct ligation (BDL). Methods: BDL (2 weeks) was performed in ovariectomized rats and the proliferative and apoptotic activity compared with normal, with BDL control rats, and with BDL +/- OVX rats treated with 17-beta estradiol. Results: OVX induced a significant (P < 0.01) reduction of bile duct mass in BDL rats. The reduction of bile duct mass induced by OVX was associated with a decreased expression of estrogen receptor (ER)-alpha (2.5-fold) and, mainly, ER-beta (35-fold). Proliferating cellular nuclear antigen (PCNA) expression in cholangiocytes was impaired by OVX, indicating depression of proliferation, whereas terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and Fas positivity were markedly enhanced, indicating activation of Fas-mediated apoptosis. Administration of 17-beta estradiol during BDL in OVX rats induced a normalization of bile duct mass, ER expression, cholangiocyte proliferation, and apoptosis (Fas and TUNEL) in comparison with untreated BDL rats. Conclusions: Our findings support the role of endogenous estrogens in sustaining the enhanced proliferative and secretory activities of cholangiocytes in cholestasis. On the basis of these data, the hypothesis of an estrogenic functional deficiency in chronic cholestatic liver diseases should merit careful attention