The Refractory State of Luteal Cells Isolated from Rhesus Monkeys after Prolonged Exposure to Chorionic Gonadotropin during Early Pregnancy

Abstract

To assess the regractory state of the rhesus monkey corpus luteum following 2–3 weeks exposure to endogenous macaque chorionic gonadotropin (mCG) in early pregnancy, we investigated in vitro the effect of hCG, dibutyryl cyclic AMP (dbcAMP) and pregnenolone on progesterone production by luteal cells isolated from monkeys during early pregnancy (Days 22–29 of gestation). For comparison, luteal cells obtained during the menstrual cycle (Days 16-19 postmenses) and at term pregnancy (Days 160–165 of gestation) were also studied. Under control conditions, luteal cells obtained on Days 22–24 of pregnancy produced significantly (P<0.01) less progesterone than cells from midluteal phase of the menstrual cycle, despite little difference in the weight of corpora lutea excised at these 2 stages. However, a marked (P<0.01) decline in luteal weight was observed between Days 22–24 and 26–29 of pregnancy, which was associated with a further reduction in luteal cell progesterone production in vitro. Maximal stimulatory doses of hCG (27 nM) and dbcAMP (1 mM) were equally effective in enhancing (P<0.01) progesterone production by luteal cells from the menstrual cycle. The combination of hCG and dbcAMP elicited no greater response. Whereas luteal cells from Days 22–24 of pregnancy failed to respond to hCG, exposure to dbcAMP significantly (P<0.01) increased progesterone production. By Days 26–29 of pregnancy, isolated luteal cells failed to respond to either hCG or dbcAMP. In contrast, progesterone production by luteal cells from term pregnancy was significantly (P<0.01) enhanced by both hCG and dbcAMP. The addition of 1 μM pregnenolone markedly (P<0.01) increased progesterone production by luteal cells from both midluteal phase of the cycle and early pregnancy. However, the progesterone synthetic activity of cells from Days 22–24 and 26–29 of pregnancy was only 20 and 5%, respectively, of that of luteal cells from the menstrual cycle, during incubation with pregnenolone. By Days 160–165 of pregnancy, progesterone production by luteal cells, in the presence and absence of pregenolone, was similar to that of cells from the menstrual cycle. The data indicate that the gonadotropin refractory state of the rhesus monkey corpus luteum following prolonged exposure to mCG in early pregnancy may include an impairment of the gonadotropin receptor-adenylyl cyclase system in luteal cells and a reduction in enzyme activity necessary for progesterone synthesis. The refractory condition of the corpus luteum appears to be reversible since gonadotropin-sensitive progesterone production is characteristic of rhesus monkey luteal cells at term pregnancy.