Intraluteal infusions of prostaglandins of the E, D, I, and A series prevent PGF(2α)-induced, but not spontaneous, luteal regression in rhesus monkeys

A luteotropic role for prostaglandins (PGs) during the luteal phase of the menstrual cycle of rhesus monkeys was suggested by the observation that intraluteal infusion of a PG synthesis inhibitor caused premature luteolysis. This study was designed to identify PGs that promote luteal function in primates. First, the effects of various PGs on progesterone (P) production by macaque luteal cells were examined in vitro. Collagenase-dispersed luteal cells from midluteal phase of the menstrual cycle (Day 6 - 7 after the estimated surge of LH, n = 3) were incubated with 0 - 5000 ng/ml PGE₂, PGD₂, 6βPGI₁ (a stable analogue of PGI₂), PGA₂, or PGF(2α) alone or with hCG (100 ng/ml). PGE₂, PGD₂, and 6βPGI₁ alone stimulated (p < 0.05) P production to a similar extent (2- to 3-fold over basal) as hCG alone, whereas PGA₂ and PGF(2α) alone had no effect on P production. Stimulation (p < 0.05) of P synthesis by PGE₂, PGF₂, and 6βPGI₁ in combination with hCG was similar to that of hCG alone. Whereas PGA₂ inhibited gonadotropin-induced P production (p < 0.05), that in the presence of PGF(2α) plus hCG tended (p =0.05) to remain elevated. Second, the effects of various PGs on P production during chronic infusion into the CL were studied in vivo. Saline with or without 0.1% BSA (n = 12), PGE₂ (300 ng/h; n = 4), PGD₂ (300 ng/h; n = 4), 6βPGI₁ (500 ng/h; n = 3), PGA₂ (300 ng/h, n = 4), or PGF(2α) (10 ng/h; n = 8) was infused via osmotic minipump beginning at midluteal phase (Days 5 - 8 after the estimated LH surge) until menses. In addition, the same dose of PGE, PGD, PGI, or PGA was infused in combination with PGF(2α) (n = 3 - 4/group) for 7 days. P levels over 5 days preceding treatment were not different among groups. In 5 of 8 monkeys receiving PGF(2α) alone, P declined to < 0.5 ng/ml within 72 h after initiation of infusion and was lower (p < 0.05) than controls. The length of the luteal phase in PGF(2α)-infused monkeys was shortened (12.3 ± 0.9 days; mean ± SEM, n = 8; p < 0.05) compared to controls (15.8 ± 0.5). Intraluteal infusion of PGE, PGD, PGI, or PGA alone did not affect patterns of circulating P or luteal phase length. In contrast, intraluteal infusion of PGE, PGD, or PGA in combination with PGF(2α) maintained P levels during the infusion period and prevented the premature menses seen with infusion of PGF(2α) alone. Although P levels were consistently lower than controls during 3 days after initiation of 6βPGI₁ plus PGF(2α) infusion, luteal phase length in these monkeys was similar to controls. Thus, PGs that stimulate steroidogenesis in vitro will prevent premature luteolysis induced by exogenous PGF(2α) was antigonadotropic in vitro, it did not suppress luteal function in vivo, but counteracted the luteolytic effect of exogenous PGF(2α).