SUMMARY Tracer kinetic techniques were used to determine the metabolic clearance rate (MCR) and production rate (PR) of progesterone in the sheep during pregnancy, the oestrous cycle and the lactation anoestrus. The MCR from whole blood measured by the continuous infusion of [3H]progesterone was 3·483 ± 0·126 l/min in pregnancy, 2·752 ± 0·239 l/min in the oestrous cycle and 5·020 ± 0·566 l/min in lactation anoestrus. After correcting for body weight the respective values were 0·077, 0·077 and 0·133 l/min/kg. The PR ranged from 0·60 to 6·75 μ/min in the oestrous cycle and 6·66 to 72·14 μg/min in pregnancy. In the last 4 weeks of gestation the PR of progesterone was significantly greater in ewes bearing foetuses with birth weights of more than 4 kg than in ewes with smaller lambs. The conversion or isotope concentration ratio of progesterone to 20α hydroxypregn-4-en-3-one (20α-diHP) was 69·4±10·0% in non-pregnant and 77·2 ± 4·8% in pregnant sheep. The concentrations of [3H]progesterone and [3H]20α-diHP were closely correlated. There was an appreciable extraction (25·4 ± 3·0%) of progesterone and production (9·1 ± 2·0% of 20α-diHP by the head.

SUMMARY The uptake and extraction of progesterone and 20α-dihydroprogesterone (20α-diHP) by the splanchnic region and by some extra-splanchnic organs was measured by the determination of the concentration of labelled progesterone and 20α-diHP in a carotid artery and in the portal, hepatic, uterine, ovarian and adrenal veins during continuous intravenous infusion of [3H]progesterone. The efficiency of splanchnic extraction of progesterone and 20α-diHP was 92 and 91%. The splanchnic clearance rates of progesterone and 20α-diHP were 1·210 and 1·223 l/min, respectively. Splanchnic clearance accounted for 27·1% of the metabolic clearance rate of progesterone. The efficiency of extraction of progesterone by some extra-splanchnic organs ranged from 7·9–45·9% across one uterine horn, 5·8–29·9% across one ovary and 30·9–33·3% across one adrenal. For the extraction of 20α-diHP the values were 6·1–9·4% (uterine horn), 15·5% (ovary) and 18·3% (adrenal). In some experiments there was a small production of 20α-diHP across the uterus and ovary. As the blood flow was a relatively small proportion of cardiac output, the clearance rate of progesterone by any one of these sites was less than 0·2% of the metabolic clearance rate. Labelled progesterone and labelled 5α-pregnanedione were retained in the endometrium (but not in the myometrium) at much higher concentrations than those found in arterial or uterine venous blood. The reduced form, 20α-dihydroprogesterone, was retained in neither the endometrium nor the myometrium. There was a high concentration of polar, conjugated metabolites of progesterone in both uterine tissues compared with that in blood. The results show that the high metabolic clearance rate of progesterone in the sheep is only partially due to splanchnic (mainly hepatic) uptake, and that over 70% of the progesterone produced is catabolized by extra-splanchnic organs.

The rates of metabolism of progesterone and 20alpha-dihydroprogesterone (20alpha-diHP) in sheep have been measured during and after the infusion of tracer amounts of [3H]progesterone. There were significant differences in the blood concentration of [3H]progesterone between experiments, but these were not attributable to the stage of gestation or to the difference between pregnant and non-pregnant animals. The mean (+/- S.E.M.) metabolic clearance rate of progesterone was 3-277 +/- 0-239 litres blood/min. The simplest model of the distribution of progesterone was one containing two pools, V1[P] and V2[P], where [p] is the blood concentration of progesterone, and in 23 experiments on 7 sheep the mean pool dimensions were 7-8[P] mug and 70[P] mug, respectively. This model was developed to include the formation of 20alpha-diHP from progesterone. Progesterone appeared to be the major source of 20alpha-diHP, though this did not seem to be an obligatory metabolite. The parameters obtained gave comparably low residual deviations for both labelled steroids and were consistent with other observations made on progesterone clearance.

The dynamics of progesterone uptake and metabolism in the mammary gland of the goat have been measured and related to the metabolic clearance rate and production rate of the hormone determined by tracer kinetic techniques. The metabolic clearance rate of progesterone from blood was 3-13 plus or minus 0-35 (S.E.M.) 1/min in ten experiments on six goats; values tended to be slightly higher in pregnant than in non-pregnant goats. The production rate of progesterone at oestrus, and at day 3 of the normal cycle, was less than 0-01 mug/min. During the luteal phase of the oestrous cycle the production rate was 8-5 and 14-6 mug/min in 2 animals, and in the second half of pregnancy, 15-3 plus or minus 0-6 mug/min (5 animals). Progesterone was extracted from the circulation by the mammary gland of conscious goats with an efficiency of 49-4 plus or minus 11-3% in non-pregnant, and 51-7 plus or minus 11-5% in pregnant aniamals. The mean clearance rate of progesterone by the udder was 0-279 1/min, 8-8% of the metabolic clearance rate. Mammary uptake of progesterone in goats with an actively secreting corpus luteum was 0-64 plus or minus 0-29 mug/min, which gave an estimated value of 0-11-1-88 ng/min/g mammary gland. The mammary extraction of progesterone was investigated in a goat 3 days after oestrus when any high affinity receptor sites would presumably be unoccupied. During the infusion of progesterone into a mammary artery, tissue sample were taken from various organs, including the mammary gland, and the concentration of labelled compounds at steady state was determined. A high mammary extraction of progesterone was found to be determined. A high mammary extraction of progesterone was found to be attributable principally to progesterone metabolism. The metabolites of progesterone were removed from the gland in venous blood and were not stored to any appreciable extent in mammary tissue. Experiments in vitro confirmed the findings in vivo that mammary tissue metabolized labelled progesterone and also pregnenolone and androstenedione; metabolism of dehydroepiandrosterone, oestradiol-17 beta, oestrone and cortisol was relatively small. Confirmation of our previous finding that the mammary gland of the goat can synthesize progesterone from labelled pregnenolone infused into the gland in vivo, further implicated this organ as an active site of metabolism of certain steroids. The physiological role of steroid metabolism in the mammary gland is discussed.