Physiological role of prostaglandin and cortisol during early pregnancy in sheep

Pregnancy failure during the early stage of gestation is a major cause of infertility in domestic ruminants. Most early pregnancy losses are characterized by endometrial dysfunction, asynchrony between the conceptus (embryo and outer trophectoderm) and uterus, or failure in conceptus development. During early pregnancy in sheep, endometrial functions are primarily regulated by ovarian progesterone (P4) and interferon tau (IFNT) from the conceptus trophectoderm. The endometrium and conceptus synthesize prostaglandins (PGs) via prostaglandin synthase two (PTGS2) and cortisol via hydroxysteroid (11-beta) dehydrogenase 1 (HSD11B1). The central hypothesis is that endometrial functions supporting conceptus elongation in ruminants are regulated by hormones produced by the ovary (P4), conceptus (IFNT, PGs, and cortisol) and perhaps endometrium itself (PGs, cortisol). The hypothesis was addressed by determining the physiological roles of: (1) PTGS2 and PGs in conceptus development; (2) PTGS2-derived PGs in P4, IFNT and cortisol regulation of endometrial function; (3) HSD11B1 and cortisol in conceptus elongation; and (4) HSD11B1-derived cortisol in P4, IFNT and PGs regulation of endometrial function. Functional studies utilizing osmotic pumps were conducted to infuse selective agents inhibiting PG biosynthesis and/or cortisol production in utero or to deliver pregnancy levels of hormones (IFNT, PGs, and cortisol) directly into the uterine lumen of sheep. Results of the studies established that: (1) PGs and cortisol are important regulators of conceptus elongation; (2) PGs mediate, in part, effects of P4 and IFNT on endometrial gene expression and function; (3) PGs stimulate endometrial HSD11B1 expression and cortisol production; (4) cortisol regulates conceptus elongation; (5) cortisol modulates effects of ovarian P4 on endometrial gene expression; (6) cortisol stimulates endometrial PTGS2 activity and PG production. Collectively, results of these studies support the idea that PGs and cortisol are important regulators of endometrial function and conceptus elongation during early pregnancy in ruminants. Knowledge gained from these studies provides new insight into the physiological pathways governing interactions between the conceptus and its uterine environment. Information from these studies provides a foundation for future translation research that is necessary to increase fertility of domestic ruminants.