There is ample evidence that prostaglandin F2alpha (PGF2alpha) is a luteolytic substance in sows, however, there is also some evidence that it may stimulate progesterone (P4) secretion in young corpora lutea (CL). In vitro studies also suggested that tumor necrosis factor alpha (TNF) is inhibitory to luteal cell P4 and estradiol-17beta (E2) release. Since E2 is a strong luteotropic substance in porcine CL, we studied the effects of intraluteal application of PGF2alpha and TNF alone and in combination on the secretion of P4 and E2 in freely moving sows. Furthermore, the effects of intraluteal infusion of E2 and its stereoisomer, estradiol-17alpha, on luteal function, were also determined. Microdialysis systems were implanted into CL at Day 10 of the estrous cycle. After a 24-h recovery period, PGF2alpha (10(-6) M) or E2 (10(-6) M) was applied daily for 6 h into the CL. PGF2alpha caused a stimulation of E2 and P4, and E2 also stimulated P4 secretion at Days 11 and 12, but the stimulatory effect of both substances diminished as the CL approached luteolysis. Intraluteal TNF application resulted in a transient increase of P4 secretion, which was followed by a dramatic reduction of P4 release. When TNF-pretreated CL were exposed to PGF2alpha at Day 11 of the estrous cycle, the prostaglandin was no longer able to stimulate but rather inhibited E2 and P4 secretion. Intraluteal application of estradiol-17alpha had no effect on P4 secretion. These results are suggestive that the PGF2alpha-induced E2 secretion in young and middle-aged CL is stimulatory to P4 secretion. Under the influence of macrophage-derived TNF production, E2 secretion is inhibited, and thereby PGF2alpha and TNF cause functional luteolysis.

Corpora lutea of all species investigated so far, including the human, produce oxytocin and a variety of other regulatory peptides. The role of these peptides is largely unknown. The subtypes of large luteal cells are able to produce tumour necrosis factor (TNF) and at the end of the luteal phase TNF-producing macrophages invade the aged corpus luteum, indicating that this cytokine may be involved in the process of luteolysis. The present contribution reviews briefly the known functions of oxytocin and substance P in the corpus luteum and then elaborates the possible involvement of luteal and macrophage TNF during luteolysis. Oxytocin applied to intact corpus luteum stimulates the secretion of progesterone and oestradiol. The stimulation of progesterone secretion by oxytocin is due to the stimulated oestrogen production. TNF, when tested in vitro, inhibits both luteal cell progesterone and oestradiol production. The TNF-mediated inhibition of aromatase activity therefore prevents the luteotrophic effects of a variety of peptides including oxytocin. This appears to be the mechanism by which TNF induces luteolysis.

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The process of luteolysis involves in most species temporarily linked functional as well as structural luteolysis. At thls time the corpus luteum (CL) produces and releases less and less progesterone and in some species also oestradrol and the morphology of the regressing CL changes such that at the end of the luteal phase no steroid-producing cells are present any more. In sheep, cows and sows both processes require an intact uterus and it has been made probable that PGF2, released by the aging endometrium is one of the initial steps inducting luteolysis (McCracken et al. 1973, Baird et al. 1976, Auletta and Flint 1988. Furthermore, it is known that cells deriving from the white blood cell line invade the aging CL (Bagavandoss et al. 1988, Henke et al. 1994 where they produce most likely cytokines. It was therefore tempting to us to study whether PGF2, and macrophage cytokines, particularly tumor necrosis factor a (TNF) participate by interacting in the process of functional luteolysis. Since structural reorgamzation of tissue often involves programmed cell death (apoptosis) and collagenase activation we studred also the ef€ects of PGF2, and TNF on apoptosis and gene expression and release of collagenases by cultivated porcine luteal cells.-+ P+--2 Fig. 1. Effects of PGF2, on progesterone and oestradiol secretion in vitro in the young corpus luteum Fig. 1 details highly schematically the ef€ects of PGF2, on progesterone (P) and oestradiol (E2) secretion under in vitro luteal cell culture conditions (for review: Pitzel et al. 1993a and b). The icosanoid has a direct mhibitory effect on P production and secretion. Simultaneously E2 production and secretion is largely stimulated. When E2 is added to the culture medium it has a stimulatory effect on P secretion. When PGF2, is applied into intact luteal tissue either under in vivo conditions or into pieces of porcine CL kept under organ culture condrtions, it has a profound stimulatory effect on E2 and surprisingly also on P secretion. Similarly, E2 stimulated P secretion (Jarry et al. 1990, Wuttke et al. 1993). Hence, we face the situation that PGF2, exerts direct inhibitory effects on P secretion but via the stimulated E2 secretion it counteracts its drect inhibitory effect. In Fig. 1 the thickness of the arrows indicates the strength of the direct inhibitory and of the indirect E2-mediated stimulatory effects of PGF2, on P secretion in the intact CL. In l l l y functional CL the E2-mediated indirect stimulatory effect appears to be stronger than the direct inhibitory effect which accounts for the stimulated E2 and P secretion when PGF2, is applied in the intact CL. l h s explanation led us to the worhng hypothesis that at the end of the luteal phase functional luteolysis is mediated by a paracrine acting substance which inhibits intraluteal E2 production and release. In search for such substances we tested the effects of a variety of cytokines including TNF and found that interleukin II, but most prominantly TNF, inhibited not only E2 secretion (Pitzel et al. 199...

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