No abstract

Ovarian stimulation is associated with a higher risk of low birth weight. However, the precise mechanisms by which ovarian stimulation increases the chances of low birth weight remain unclear. In this mouse model study, in vivo developed blastocysts that were not exposed to gonadotropins were transferred into pseudopregnant females that had mated naturally (the control group), pseudopregnant females that had been administered a low dose of ovulation‐stimulating hormone (the L‐SO group) and pseudopregnant females that had been administered a high dose of ovulation‐stimulating hormone (the H‐SO group). The embryo implantation rate and fetal weight were significantly lower in the L‐SO and H‐SO groups than in the control group. The density of Dolichos biflorus agglutinin (DBA)+ uterine natural killer (uNK) cells in the decidua basalis was significantly lower in the L‐SO and H‐SO groups than in the control group. Ovarian stimulation also downregulated a variety of cytokines related to uNK cells that are involved in placental angiogenesis and trophoblast invasion. Collectively, our findings indicate that ovarian stimulation impairs DBA+ uNK cell density in the decidua basalis, which may downregulate uNK‐related cytokine secretion and influence placental angiogenesis and restrict fetal growth in mice.

Ovarian stimulation is associated with an increased incidence of abnormal placentation. Uterine natural killer (uNK) cells are the major subpopulation of decidual immune cells, which are crucial for placentation. In a previous study, we found that ovarian stimulation impairs uNK cell density on gestation day (GD) 8.5 in mice. However, it was not clear how ovarian stimulation led to a reduction in the density of uNK cells. In this study, we constructed two mouse models, an in vitro mouse embryo transfer model and an estrogen-stimulated mouse model. We used HE and PAS glycogen staining, immunohistochemical techniques, q-PCR, Western blot, and flow cytometry to analyze the mouse decidua and placenta, and the results showed that SO resulted in a fetal weight reduction, abnormal placental morphology, decreased placental vascular density, and abnormal density and function of uNK cells. Our results suggest that ovarian stimulation resulted in aberrant estrogen signaling and may contribute to the disorder of uNK cells caused by ovarian stimulation. Together, these results provide new insights into the mechanisms of aberrant maternal endocrine environments and abnormal placentation.

Background Ovarian stimulation is associated with an increased incidence of abnormal placentation. Uterine natural killer (uNK) cells are the major subpopulation of decidual immune cells, which are crucial for placentation. In a previous study, we found that ovarian stimulation impairs uNK cell density on gestation day (GD) 8.5 in mice. However, it is not clear how ovarian stimulation led to a reduction in the density of uNK cells. In this study, we transferred blastocysts that were obtained from natural mating and in vivo development into individual pseudopregnant recipients produced by either natural mating (control group) or mating following ovarian stimulation (SO group). Materials and Methods Results The fetal weights of the SO group were significantly lower than those of the control group on GD 18.5 (P < 0.001). In the SO placentas, PAS−positive area was significantly expanded (P < 0.05), and the micro vessel density values at the labyrinth zone were significantly reduced (P < 0.05). Notably, the density, maturity and cell proliferation activity of PAS+DBA+ uNK cells significantly declined in SO pregnant uteri compared with control, and the production of cytokines including IFN-γ, VEGF and PLGF of CD45+CD3−DBA+ uNK cells was also attenuated by ovarian stimulation. Additionally, we demonstrated that the production of chemokines and cytokines related to uNK recruitment, proliferation, and differentiation in the decidua is suppressed by ovarian stimulation. Conclusion we found that ovarian stimulation resulted in aberrant estrogen signaling and may contribute to the disorder of uNK cells caused by ovarian stimulation. Together, these results provided new insights on the mechanisms of aberrant maternal endocrine environments and abnormal placentation.