Abruption-induced preterm delivery is associated with thrombin-mediated functional progesterone withdrawal in decidual cells.
Plasma progesterone levels remain elevated throughout human pregnancy, suggesting that reduced reproductive-tract progesterone receptor (PR) initiates labor. Placental abruption and excess thrombin generation elicit preterm delivery (PTD). PR, glucocorticoid receptor (GR), and total and p-ERK1/2 in decidual cells (DCs) and interstitial trophoblasts (IT) were assessed via immunohistochemical staining in abruption-associated PTD versus gestational-age matched control placentas, and in cultured DCs incubated with estradiol (E2) ± medroxyprogesterone acetate (MPA) ± thrombin. Immunostaining for PR was lower in DC nuclei in abruption versus control decidua and was absent from ITs; GR was higher in IT than DCs, with no abruption-related changes in either cell type; p-ERK1/2 was higher in DCs in abruption than control decidua, with total ERK 1/2 unchanged. Immunoblotting of cultured DCs demonstrated strong E2, weak MPA, and intermediate E2+MPA mediated elevation of PR-A and PR-B levels, with constitutive GR expression. In cultured DCs, thrombin inhibited PR but not GR mRNA levels, reduced PR binding to DNA and [(3)H]progesterone binding to PR, and enhanced phosphorylated but not total ERK1/2 levels. Coincubation with a specific p-ERK1/2 inhibitor reversed thrombin-enhanced p-ERK1/2 and lowered PR levels. Thus, abruption-associated PTD is initiated by functional progesterone withdrawal, as indicated by significantly reduced DC nuclear expression of PR-A and PR-B. Functional withdrawal of progesterone results in increased p-ERK1/2, and is thus one pathway initiating abruption-associated PTD.
Department of Obstetrics and Gynecology, Ohio State University College of Medicine, 460 West 12th Ave., Columbus,OH 43210, USA.
Charles J
CJ
Lockwood
Umit A
UA
Kayisli
Carlos
C
Stocco
William
W
Murk
Emre
E
Vatandaslar
Lynn F
LF
Buchwalder
Frederick
F
Schatz
D000037:Abruptio Placentae / Q000235:genetics / Q000473:pathology*; D015153:Blotting, Western; D002457:Cell Extracts; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003656:Decidua / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D004958:Estradiol / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics / Q000473:pathology*; D011374:Progesterone / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*
D002457:Cell Extracts; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D011374:Progesterone; D004958:Estradiol; D004247:DNA; D017258:Medroxyprogesterone Acetate; D048049:Extracellular Signal-Regulated MAP Kinases; D013917:Thrombin