Loss of inhibin negative feedback to pituitary gonadotropes leads to enhanced ovulation but pregnancy failure in mice

Abstract Follicle-stimulating hormone (FSH) is an essential regulator of ovarian function. Inhibins are TGFβ family ligands produced in the gonads that suppress FSH synthesis by pituitary gonadotrope cells. Inhibins require a co-receptor, betaglycan or TGFBR3L, to mediate their actions. Female mice with a gonadotrope-specific knockout of betaglycan or global deletion of Tgfbr3l have increased FSH activity or levels and produce larger litters compared to controls. Females with both co-receptors knocked out (hereafter dKO) have dramatically increased circulating FSH, ovulate about 4 times as many eggs in natural cycles as controls but are infertile. Here, we show that dKO females show an increased number of implanted embryos at 7.5 days post coitum (dpc) but that their pregnancies fail around mid-gestation. Wild-type surrogates give birth to live young following transplantation of embryos from control or dKO females. Conversely, control but not dKO females can carry wild-type embryos to term, suggesting that the maternal environment in dKO mice cannot support full term pregnancies. Elevated estradiol levels are deleterious to pregnancy in mice, and we detected increased estradiol production in ovaries of pregnant dKOs. Treatment of these animals with aromatase inhibitors or a selective estrogen receptor degrader increased fetal survival. The results indicate that loss of inhibin action in murine gonadotropes results in excess estradiol during pregnancy that precludes successful pregnancy.