Partial Progesterone Deprivation Affects the Expression of Apoptosis-Specific Genes and Proteins in a Zone-Specific Manner in Rat Placenta.

Background Progesterone maintains the well-being of both the placenta and the fetus. Low maternal progesterone levels are strongly correlated with smaller placentas and fetal growth restriction. Aim To investigate the possible effects of reduced progesterone levels-induced placental zone-specific apoptosis mechanisms, which may contribute to intrauterine growth retardation (IUGR). Methods Sprague-Dawley rats were divided into three groups (control, progesterone-reduced, and progesterone-restored groups). On gestation day (dg) 15, ovariectomy was performed in the progesterone-manipulated groups, and a subcutaneous mini pump was implanted to release estradiol (40 ng/h). Estradiol was also injected twice daily from 17-20 dg. The progesterone-reduced rats received approximately one-third of the average progesterone level daily from 15 dg to maintain the normal pregnancy. Maternal progesterone levels, fetal and placental weights, and the expression of placental pro- and anti-apoptotic markers (Tumor protein p53 (p53), Cyclin-dependent kinase inhibitor 1 (p21), p27Kip1 (p27), BCL2-associated X protein (Bax), B-cell lymphoma 2 (Bcl2), β-catenin, and cyclin D1) were measured on 16, 19, and 21 dg. Key results A 37% reduction in progesterone level was observed in the progesterone-reduced group on 19 dg. This decline was associated with a significant decrease in both whole placental and basal zone weights, while the fetal body weight and labyrinth zone weight remained unchanged. These changes occurred concurrently with increased placental expression of proapoptotic markers (p53, p21, p27, Bax) and antiapoptotic markers (cyclin D1 and Bcl2) in both placental basal and labyrinth zones at 16, 19, and 21 dg. Progesterone restoration recovered most of the molecular changes that emanated from its withdrawal. Conclusion The modulatory effect of progesterone did not result in improved fetal body weight, likely due to the variable impact of progesterone on the expression of pro- and anti-apoptotic proteins within the labyrinth and basal zones across different gestational days. Implication: These findings indicate that the effect of progesterone on cell death and survival pathways is zone-specific, reflecting different regulatory mechanisms within different placental regions.