Metabolic Clearance and Production Rates of Progesterone in Non-pregnant and Pregnant Baboons (Papio papio) EUGENE D. ALBRECHT AND JOHN D. TOWNSLEY Pregnancy Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20014 in pregnant animals and 5.9 ± 2.2 ng/ml during the luteal phase of the menstrual cycle. The mean (± SE) calculated progesterone production rates (MCR x serum progesterone concentration) were 4.57 ± 1.74 mg/day during the luteal phase of the menstrual cycle and 15.26 ± 2.48 mg/day during the last two-thirds of gestation. Thus, increased serum progesterone concentrations in pregnant baboons reflect enhanced production rather than decreased clearance. This is analogous to humans, but contrasts with rhesus monkeys, in which production is not increased during pregnancy. The elevated baboon progesterone MCR, despite increased serum corticosteroid binding capacity, indicates that other factors such as changes in maternal metabolism may also be important in regulating progesterone clearance. (Endocrinology 99: 1291, 1976)

ABSTRACT. The metabolic clearance rate (MCR) of progesterone was examined in the baboon to determine whether the increased serum progesterone concentrations during gestation result from increased production or decreased clearance. MCR was determined by constant infusion of [3H]progesterone in 6 non-pregnant baboons and 13 pregnant animals, between 58 and 175 days gestation. Progesterone MCR (mean ± SE) was significantly greater in pregnant (1316 ± 105 I/day, P < 0.025; 87.3 ± 6.2 I/day/ kg, P < 0.01) than in non-pregnant animals (893 ± 75 I/day; 53.1 ± 3.5 1/day/kg). There was no correlation between progesterone MCR and gestational age. Mean (± SE) progesterone MCR was similar during the follicular (983 ± 119 I/day; 58.8 ± 3.8 1/day/kg) and luteal (802 ± 78 I/day; 52.4 ± 6.8 1/day/kg) phases of the menstrual cycle. Serum progesterone concentrations (mean ± SE), determined by radioimmunoassay, were 11.3 ± 1.2 ng/ml

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ERUM PROGESTERONE CONCENTRATION increases significantly during pregnancy in the baboon (1). To determine whether this is a result of increased production, or decreased clearance, the metabolic clearance rate (MCR) of progesterone was determined in non-pregnant and pregnant animals. A decrease in progesterone clearance might be anticipated since serum cortisol binding capacity, indicative of corticosteroid binding globulin (CBG) which binds circulating progesterone (2), is increased in baboon pregnancy (3). Serum progesterone concentrations were determined in the present study and the serum production rates of progesterone calculated. Materials and Methods

Animals Female baboons (Papio papio) were supplied by the Veterinary Resources Branch, Division of Received April 7, 1976.

Research Services, NIH, and maintained and mated as described previously (4). Three animals were studied during the follicular phase and three during the luteal phase of the menstrual cycle, as judged by menstrual history and turgescence of external sex skin. Thirteen pregnant animals with accurately timed gestations (±2 days) were each studied once between 58 and 175 days of gestation. All pregnancies appeared uncomplicated and resulted in vaginal deliveries of viable newborns close to term (182 ± 2 days, mean ± SE) except for 1 pregnancy, which was interrupted by a cesarean section because of the requirements of another protocol. Gestational ages were normalized to 184 days, the mean gestational length for the colony. Metabolic clearance rate (MCR) of progesterone [4-14C]Progesterone (SA 52.8 Ci/mole) and [7-3H]progesterone (SA 24 Ci/mmole) obtained from New England Nuclear Corporation, were purified by column chromatography prior to use. The MCR of progesterone was determined by a continuous infusion method (5,6). Animals were initially sedated between 1200 and 1300 h with 100 mg Ketamine HC1 im (100 mg/ml, Bristol Labs) after brief restraint in a squeeze cage.

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Endo • 1976 Vol 99 • No 5

ALBRECHT AND TOWNSLEY

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They were placed on their left side and Ketamine HC1 (3.15 mg/min/0.42 ml 5% dextrose) was infused with an I-Med 922 infusion pump (I-Med Corporation, San Diego, California) via a catheter (Bard 1917 R, 24 in) into the saphenous vein. Animals were covered with a heating pad maintained at 38 C. A priming dose of approximately 3.5 /xCi [3H]progesterone in 4 ml 4% ethanol:normal saline was administered via a catheter (Bard 1819 R, 12 in) into the antecubital vein. Ten minutes later a constant infusion of [3H]progesterone (0.11 /xCi/min/0.42 ml 4% ethanol:normal saline) was administered into the antecubital vein. Progesterone was infused from glass syringes through medical grade Teflon connecting tubing using a Harvard pump (Harvard Instrument Company, Dover, Massachusetts). Preliminary experiments showed that approximately 10% [3H]progesterone is adsorbed by the syringe and tubing. The rate of [3H] progesterone infusion, however, was constant when determined at the beginning and end of TABLE

Animal no. Non-pregnant 3087 B579 B439 B546 B418 X312 X±SE Pregnant X444 67285 3297 X254 X311 1187 X432 B222 1207 0941 0801 2577 4216 X±SE

each experiment, from the average dpm [3H]progesterone in 6 consecutive 1 min collections from the catheter tip. Three 7 ml blood samples were removed via the saphenous vein catheter at 70, 80 and 90 min following the onset of continuous infusion. Isotopic equilibrium was attained within 70 min as established by progesterone infusion for 180 min. The coefficients of variation of serum [ 3 H]progesterone concentration determined at 70, 80 and 90 min of constant infusion were 7.1 and 10.3% in pregnant and nonpregnant animals, respectively (Table 1). There was no evidence of increasing or decreasing serum [ 3 H]progesterone during that period. Blood samples were kept in ice until centrifuged and serum was stored at - 2 0 C. [14C]Progesterone (approx. 250 dpm) was added to duplicate 1.0 ml serum samples for estimation of procedural losses and samples were extracted twice with 5 ml petroleum ether (Fisher) from newly opened bottles. The extracts were applied to 0.7 x 9 cm

1. Metabolic clearance rate (MCR) and production rate (PR) of serum progesterone (P) in non-pregnant and pregnant baboons

Phase of menstrual cycle or gestational age (days)

(1/day/kg)

CV a (%)

P (ng/ml)

829 902 1,219 662 931 815 893 ± 75

57.0 46.2 58.3 40.5 64.0 52.8 53.1 ± 3.5

12.7 15.4 7.7 2.8 16.6 6.6 10.3

c

Metabolic clearance and production rates of progesterone in non-pregnant and pregnant baboons (Papio papio).

Metabolic Clearance and Production Rates of Progesterone in Non-pregnant and Pregnant Baboons (Papio papio) EUGENE D. ALBRECHT AND JOHN D. TOWNSLEY Pr...
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