OR09-03 Loss of Inhibin Negative Feedback In The Pituitary Leads To Enhanced Ovulation But Pregnancy Failure In Mice

Disclosure: Y. Lin: None. E. Brule: None. M. Cowan: None. U. Boehm: None. D.J. Bernard: None. Loss of inhibin negative feedback in the pituitary leads to enhanced ovulation but pregnancy failure in mice Follicle-stimulating hormone (FSH) is an essential regulator of gonadal function, particularly in females. Inhibins are TGFβ family ligands made in the gonads that suppress FSH synthesis. Inhibins require a co-receptor, betaglycan or TGFBR3L, to mediate their actions in pituitary gonadotrope cells. Female mice with a gonadotrope-specific knockout of betaglycan or global deletion of Tgfbr3l exhibit increased ovarian follicle development, numbers of ovulated eggs, and litter sizes compared to controls. Females with both co-receptors knocked out (hereafter dKO) show dramatic increases in FSH levels, numbers of antral follicles and corpora lutea, serum progesterone levels, and ovarian aromatase expression. They ovulate 3-4 times as many eggs in natural cycles compared to control females. dKO females can become pregnant and show an increased number of implanted embryos at 7.5 days post coitum (7.5 dpc). Nevertheless, dKO females do not give birth to live offspring. By 10.5 dpc, the weight of the fetoplacental unit is decreased in dKO females, and many embryos display morphological abnormalities. By 14.5 dpc, most embryos in dKO females are either dead or resorbing. Wild-type surrogates give birth to live young following transplantation of embryos from control or dKO females. Conversely, control but not dKO females carry wild-type embryos to term. These data suggest that the maternal environment in dKO mice cannot support full-term pregnancies. Based on the hormonal profile of the cycling females, we suspected a deleterious effect of elevated estrogens. Consistent with this idea, treatment with the aromatase inhibitor anastrozole increased fetal survival in some dKO mice, suggesting a role for estrogens in embryo death. We are currently more thoroughly characterizing the maternal hormonal environment throughout gestation and investigating placental structure/function to gain more insight into the precise nature of the pregnancy failure. Our results will show how loss of inhibin action in the pituitary impede embryo survival and whether pregnancy loss is linked to increases in FSH. Presentation: Friday, June 16, 2023