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When fetuses and placentas were removed on Day 18 in normal pregnant rabbits, plasma progesterone levels declined rapidly to non-pregnant values within 48 h. This decline was largely prevented if only fetectomy was performed, leaving the placentas in situ, but not when the fetal components of the placentas were also removed. These results suggested that ovarian progesterone production was dependent upon trophic influences emanating from the fetal portions of the placentas. Ovarian progesterone production was maintained by an extract of rabbit pituitaries for at least 72 h after removal of fetuses and placentas.

Fetectomy, either alone or combined with ovariectomy, was performed in 17 monkeys. Following fetectomy alone in 8 animals, progesterone values were maintained at normal pregnancy levels (1.0 ng/cc plasma or more), until expulsion of the placenta, which frequently occurred at a time well past normal term. Values declining toward but not reaching the nonpregnancy range were observed in some animals in the 2 to 6 weeks preceding expulsion; no similar decline occurs preceding normal labor. In all cases, after the placenta was expelled, progesterone values fell below 1 ng/cc plasma within 2 days. When ovariectomy was superimposed on 3 animals previously fetectomized, plasma progesterone values fell abruptly to nonpregnancy levels, and the placenta was expelled in an average of 6.3 days. The source of the progesterone in these fetectomized animals was, therefore, the ovaries, not the placenta damaged by a preceding fetectomy. However, the ovarian progesterone production after fetectomy was dependent on the continued presence of the placenta. In 6 animals following ovariectomy, and with an intact fetus and placenta, plasma progesterone levels were usually maintained at normal pregnancy levels. When fetectomy was superimposed in these animals with a preceding ovariectomy, plasma progesterone levels fell into the nonpregnancy range in an average of 4.8 days, and placental expulsion occurred after an average of 30.8 days. We believe this reflected a deteriorating ability of the fetectomized placenta to produce progesterone, which was capable only transiently of maintaining plasma values, but later of exerting sufficient local effect to maintain uterine quiescence for a longer time.

Our studies were designed to determine whether changing peripheral progesterone levels in rabbits reflected changing metabolic clearance rates (MCR) or changing production rates (PR), or both. Plasma progesterone concentrations rise from nonpregnancy levels to peak values at the end of the first third of gestation and at midpseudopregnancy. In the pregnant rabbit, these decline slowly during the second third of gestation and then more rapidly until near nonpregnancy values are reached at term. Progesterone levels decline sharply during the second half of pseudopregnancy. During pregnancy and pseudopregnancy, we found only small variations in MCRs which cannot account for the approximately 10-fold increase in plasma progesterone concentrations. The increases can, however, be accounted for by changes in PRs which rose sharply after conception of hCG injection to 14-fold the nonpregnancy level on day 16 of gestation and 11-fold on day 7 of pseudopregnancy. These results indicate that changes in ovarian PRs are the major factor for the variations in peripheral progesterone levels during pregnancy and pseudopregnancy. The rabbit differs in this respect from the guinea pig, in which changing progesterone concentrations during pregnancy were shown to reflect sharply reduced MCRs. After a single injection of progesterone in 20-day pregnant rabbits, the disappearance of the steroid from the circulation consisted of two components; an initial phase during which progesterone disappeared rapidly (t1/2 = 2.4 +/- 0.2 min) followed by a slower rate of disappearance (t1/2 = 21.5 +/- 2.2 min).

Peripheral plasma progesterone (P) levels in the rhesus monkey remain relatively constant both during the latter half of pregnancy and for long periods after fetectomy (removal of the fetus with the placenta left in situ) or ovariectomy. The constancy is maintained despite what appears to be reciprocal changes in the relative contributions of ovary and placenta. Placental regulation of the corpus luteum is likely, but it is not known if the corpus luteum responds to a gonadotropic stimulus in the later stages of pregnancy. In this study, we have investigated the effects of hCG administration in postdelivery monkeys (normally pregnant, fetectomized, ovariectomized and sham ovariectomized animals) and have determined if hCG administration maintains plasma P at pregnancy levels. hCG maintained P at pregnancy levels after surgical removal of the conceptus near term in both normally pregnant and previously fetectomized monkeys over a 7-day treatment period. hCG treatment after normal delivery maintained P levels in sham-ovariectomized but not in ovariectomized monkeys over an 8-day treatment period. The magnitude of the response to hCG declines over the treatment period in all groups except fetectomized monkeys, although hCG levels in the peripheral plasma are quite constant. These results indicate that the ovary of late pregnancy is fully capable of producing P at normal values and is responsive to this gonadotropin.

The metabolic clearance rate (MCR) and production rate (PR) of progesterone were measured in rhesus monkeys both before and during intravenous infusion of progesterone at rates which approximately doubled or tripled the peripheral plasma levels. The monkeys were normally pregnant or fetectomized and were studied during the second half of pregnancy. Raising the peripheral plasma levels did not significantly after the MCR or the PR of progesterone. We conclude that peripheral progesterone levels are not the factor which controls the PR of progesterone in rhesus monkeys.