The elongating sheep conceptus produces interferon tau (IFNT), prostaglandins (PGs) via PG synthase two (PTGS2), and cortisol via Type 1 11-beta-hydroxysteroid dehydrogenase (HSD11B1). The endometrial epithelia also synthesize PGs via PTGS2 and regenerate cortisol via HSD11B1 during early pregnancy. Previously, PTGS2-derived PGs were found to be essential for conceptus elongation and to mediate effects of ovarian progesterone and IFNT on endometrial functions. Here, we tested the hypothesis that IFNT, PGs and cortisol from the conceptus are important regulators of endometrial functions regulating conceptus elongation. In Study 1, bred ewes were fitted with osmotic pumps that infused PF915275 (400 μg; a selective HSD11B1 inhibitor) in vehicle (5% ethanol and 0.6% DMSO in PBS) or PF915275 and recombinant ovine IFNT (101 μg) into the uterine lumen from Days 10 to 14 post-mating (n=7/treatment). Ovoid conceptuses were recovered from PF915275-infused ewes, whereas elongated conceptuses (>12-14 cm) were present in PF915275+IFNT-infused ewes. In Study Two, cyclic ewes received infusion of vehicle as a control (CX) or pregnancy levels of IFNT (101 ug), PGs (251 ng PGE2, 409 ng PGF2a, 1483 ng PGI2), cortisol (156 ng), IFNT+PGs, IFNT+cortisol, PGs+cortisol, or IFNT+PGs+cortisol into the uterine lumen from Days 10 to 14 post-estrus (n=5/treatment). Endometrium was isolated, and expression of genes associated with elongation of the conceptus was determined by real-time PCR. Relative to CX ewes, infusion of PGs increased (P<0.05) CTSL, CST3, CST6, GRP, HSD11B1, IGFBP1 and LGALS15, and cortisol increased CTSL, GRP, HSD11B1, SLC1A5 and SLC2A1. As compared to cortisol alone, PGs+cortisol increased (P<0.05) IGFBP1, SLC5A1, SLC5A11, and SLC7A2. IFNT+PGs increased (P<0.05) CTSL, CST6, HSD11B1, IGFBP1, SLC2A1 and SLC7A2 over PGs alone, and IFNT+cortisol increased GRP over cortisol alone. These studies support the ideas that: (1) HSD11B1-regenerated cortisol is an important regulator of conceptus elongation and endometrial function during early pregnancy in sheep; (2) IFNT is a master regulator of endometrial functions important for conceptus elongation; and (3) IFNT, PGs and cortisol from the conceptus coordinately regulate endometrial functions important for conceptus growth and development during early pregnancy. Supported by AFRI Competitive Grants 2009-65203-31188 and 2012-67015-30173 from the USDA National Institute of Food and Agriculture.