Abruption-Induced Preterm Delivery Is Associated with Thrombin-Mediated Functional Progesterone Withdrawal in Decidual Cells

Abstract

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.

Prenatal Acetaminophen Affects Maternal Immune and Endocrine Adaptation to Pregnancy, Induces Placental Damage, and Impairs Fetal Development in Mice

“…41 Although functional withdrawal of progesterone and reduced nuclear expression of the progesterone receptor subtypes on human decidual cells have been proposed to contribute to the initiation of preterm delivery, 42 we did not observe preterm delivery on APAP treatment in mice.…”

Progesterone inhibits in vitro fetal membrane weakening

“…Clinical trials suggest that progestogen prophylaxis reduces the risk of preterm birth in at-risk women. 22,[44][45][46][47][48][49][50] However, observations regarding the capacity for progestogen therapy to prevent PPROM specifically are lacking. 22,[47][48][49][50] In most studies, either PPROM rates were not reported or patients with PPROM were excluded from analysis.…”

“…45 Similarly, abruptionassociated preterm delivery is associated with thrombin-mediated functional progesterone withdrawal the involves PR-A and PR-B in decidual cells. 46 There is no information on how mPRs change at the end of gestation.…”

Decidual Bleeding as a Cause of Spontaneous Hemoperitoneum in Pregnancy and Risk of Preterm Birth

“…However, no information is available on the presence or potential role of uNK cells in ectopic decidualization. While plasma progesterone levels remain elevated throughout human pregnancy, as mentioned decidual bleeding in pregnancy may be elicited by a functional progesterone withdrawal, as indicated by significantly reduced decidual cell nuclear expression of progesterone receptor-A and -B. Functional withdrawal of progesterone results in increased phospho-ERK1/2 pathway initiating decidual bleeding and causing obstetrical complications such as abruption-induced preterm delivery [44] . Mechanical as well as cellular changes can contribute to the occurrence of SHiP.…”