A Role for Oxytocin during Luteolysis and Early Pregnancy in Swine

In swine, episodic release of prostaglandin (PG) F 2α is responsible for corpus luteum (CL) regression, but the stimulus for its secretion from the endometrium has not been established. We hypothesize that oxytocin (OT) acts through specific endometrial OT receptors (OTr) to activate the phosphoinositide (PI) signaling pathway, thereby stimulating pulsatile PGFF 2α secretion which is luteolytic. When OT is administered to cyclic gilts during late diestrus (i.e., days 10‐16), interestrous interval is decreased. This effect is uterine‐dependent because OT does not promote CL regression in hysterectomized gilts. Circulating concentrations of 13, 14‐dihydro‐15‐keto PGFF 2α (PGFM; the major stable metabolite of PGFF 2α ) do not increase after OT injection on days 10 and 12, but increase 10 minutes after OT injection on days 14 and 16 in cyclic gilts. Density of endometrial OTr is correlated with OT‐stimulated PI hydrolysis (r = 0.83) and PGFF 2α secretion (r = 0.87). Endometrial inositol 1, 4, 5‐trisphosphate (IP 3 ) production increases within 30 seconds after OT treatment, and precedes the PGFF 2α release stimulated by OT. Endometrial PI hydrolysis and PGFF 2α secretion are similarly increased by AlF 4 ‐ (phospholipase C activator), but not by cholera toxin (adenylyl cyclase activator). Increased PGFF 2α secretion also occurs in response to protein kinase C activation with phorbol ester. Treatment of cyclic gilts with OT in vivo increases PI hydrolysis in response to a subsequent OT challenge in vitro, indicating that OT may upregulate, rather than down‐regulate OTr. Although glandular epithelial and luminal surface epithelial cells produce PGFF 2α in the greatest quantities, responsiveness to OT appears to reside primarily in stromal cells of the endometrium. Luminal epithelial cells are unresponsive to OT, whereas glandular epithelial display responsiveness to OT which is intermediate to that of stromal and luminal epithelial cells. In pregnant gilts, OT‐induced increases in PGFM on days 10‐16 are markedly less than for cyclic gilts on days 14 and 16. Responsiveness to OT in vitro is also reduced on day 16 of pregnancy and estradiol‐induced pseudopregnancy, and is not increased by prior treatment with OT in vivo as occurs for cyclic gilts. Collectively, these results support the hypothesis that OT stimulates phospholipase C activity to yield IP 3 and diacylglycerol (DAG) second‐messengers which promote endometrial PGFF 2α release during CL regression in pigs, as occurs for sheep and cattle. However, regulation of endometrial OTr expression and corresponding responsiveness to OT during the estrous cycle and early pregnancy appears to be markedly different than that for endometrium of ruminants.