Effects of letrozole on rat placental development.

We examined the morphological effects of letrozole on placental development in pregnant rats. Letrozole was orally administered at a repeat dose to pregnant rats at 0 mg/kg (control group) and 0.04 mg/kg (letrozole group) from gestation day (GD) 6 to GD 20. In the letrozole group, fetal mortality and placental weight increased from GD 15 onwards and GD 13 onwards, respectively. Fetal weights increased on GDs 15 and 17 but decreased on GD 21. Histopathologically, letrozole treatment induced multiple cysts lined with undifferentiated syncytiotrophoblasts in the trophoblastic septa on GD 13. These cysts then develop into dilated maternal sinusoids with congestive hyperemia, resulting in an enlarged placenta. In the metrial gland, there was a dilated lumen of the spiral artery and interstitial edema throughout the experimental period, resulting in thickened metrial gland. These changes are considered to be due to maternal blood circulation stagnation in the metrial gland, which is associated with dilated maternal sinusoids in the labyrinth zone. Thus, although letrozole induces an enlarged placenta due to congestive hyperemia of the labyrinth zone and transient increases in fetal weight, these placentas are thought to decline in function as the pregnancy progresses, leading to intrauterine growth restriction at the end of pregnancy.