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SUMMARY
The uptake of cortisol by the gastro-intestinal tract and by the liver was estimated in sheep by measurement of [3H]cortisol concentrations in portal and hepatic venous plasma during constant infusion of tritium-labelled cortisol, with simultaneous measurement of plasma flows.
The total splanchnic uptake of cortisol was 57 ± 4 (s.e.m.)% of the measured rate of cortisol secretion, 45% by the liver and the remainder by the gastro-intestinal tract. The splanchnic extraction of cortisol could be related to plasma flow, and was less efficient at higher flows. It could also be related to plasma cortisol concentration, and was more efficient at higher concentrations. The splanchnic uptake of cortisol was closely correlated with the flow of unbound cortisol into the region, and was 1·61 times that influx. There is therefore partial dissociation of plasma protein-bound cortisol during the splanchnic uptake.
About 25% of secreted cortisol is converted to cortisone at extrahepatic sites, and is removed from plasma by the liver.
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SUMMARY
Tritium-labelled cortisol was administered to sheep by intravenous infusion at constant rate for up to 4 hr. When the infusion was stopped, [3H] cortisol disappeared rapidly from plasma and its concentration could be described by a double exponential function. There was good agreement between the results from 50 experiments on 11 sheep. In pregnant ewes, there was no noticeable difference in the rate of disappearance of [3H]cortisol from plasma until about 2 weeks before lambing, when the rate became more rapid.
These data were interpreted in terms of a two-compartment model of cortisol distribution. The central compartment contains about 42 μg. cortisol and may be identical with the cortisol contained in whole blood volume. The outer compartment contains about 130 μg. cortisol; less than half of this compartment may be in intercellular fluids, partly bound to protein, and the remainder in intracellular fluids.
In pregnant ewes near term there is a decrease in plasma cortisol concentration which appears to result from expansion of plasma volume. The decrease in unbound cortisol concentration probably results in a decrease in the size of the outer compartment of cortisol. This may contribute to the observed increase in the rate of disappearance of [3H] cortisol from plasma, but this change may also coincide with the initiation of secretion of cortisol by the foetus, at about 1 or 2 μg./min.
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SUMMARY
Tritium-labelled cortisol was injected intravenously, as a single dose, in 12 experiments on seven sheep with autotransplanted left adrenal glands, in which cortisol secretion rate could be measured directly by sampling adrenal venous blood.
In all experiments, curves which represented sums of two exponential terms could be fitted to the estimates of specific activity of plasma cortisol. The interpretation of the data was based on the distribution of cortisol in two miscible pools, and the calculated rates of cortisol turnover were much greater than the cortisol secretion rates which were measured directly and simultaneously.
Simultaneous injection of Evans blue suggested that 1–2 min. was needed for complete mixing of the injected dose in plasma, during which time labelled cortisol leaves plasma with a half-time of about 1 min. It is concluded that such conditions do not provide a satisfactory basis for tracer kinetic analysis.
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SUMMARY
Tritium-labelled cortisol was infused intravenously for about 4 hr. into sheep with autotransplanted left adrenal glands. The specific activity of plasma cortisol became constant about 2 hr. after beginning the infusion, and in almost all experiments, the rate of cortisol secretion and the concentration of cortisol in plasma were constant during the remainder of the period of infusion.
The rate of cortisol turnover was calculated as the ratio of the rate of infusion of labelled cortisol and the constant specific activity which was attained during infusion. Within the limits of experimental error, the calculated rate of cortisol turnover in 55 experiments was equal to the simultaneously measured rate of cortisol secretion.
In sheep which were accustomed to handling, the rate of cortisol secretion was about 12 μg./min. and the concentration of cortisol in plasma was about 18 μg./l. The rate of cortisol secretion did not change during pregnancy in ewes, but there was a decrease in the concentration of cortisol in plasma in the last 2 weeks before lambing.
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SUMMARY
The apparent rate of cortisol turnover was determined in conscious and anaesthetized sheep by injection of tritium-labelled cortisol. Simultaneously, the rate of cortisol secretion was determined by collection of adrenal venous blood. The apparent rate of cortisol turnover was found to be two to three times the rate of cortisol secretion.
Search for other papers by CECELIA A. BEDFORD in
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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.
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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.
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ABSTRACT
Three mature Large White boars were anaesthetized and received [7(n)-3H]pregnenolone by continuous infusion into right and left spermatic arteries for up to 180 min. Spermatic venous blood flow was measured by separate timed collections of completely diverted outflow from each testis and blood not sampled was returned to the peripheral circulation.
The total radioactivity in plasma from each testis increased markedly during the first 60 min of infusion to reach a plateau from 80 to 180 min. Radiolabelling of 5α-androst-16-en-3-one, 5α-androst-16-en-3β-ol and -3α-ol showed similar patterns with ratios of mean radioactivity of 5:3:1 respectively between 80 and 180 min. In comparison, the amounts of tritiated 4,16-androstadien-3-one formed were very small. The radiolabelling of testosterone and 4-androstenedione occurred more rapidly than that of the 16-androstenes and reached maxima by 30 min. However the amounts were only one-fifth (testosterone) and one-tenth (4-androstenedione) those of the combined quantities of tritiated 16-androstenes.
Addition of human chorionic gonadotrophin (hCG) to the infusate to one testis in each animal (so that 5000 i.u. hCG were delivered in 15–20 min) produced no change in the outputs of radiolabelled steroids although radioimmunoassay of spermatic venous plasma in samples from the third experiment showed a transient increase in the concentration of 4-androstene-3,17-dione during the hCG infusion. It is suggested the lack of response to hCG could be produced by saturation and down regulation of binding sites by the very high local concentrations of hCG.
J. Endocr. (1984) 103, 179–186
Search for other papers by J. R. G. CHALLIS in
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SUMMARY
The metabolic clearance rate of oestrone from whole blood and its conversion to oestradiol-17β and oestradiol-17α were measured in pregnant and non-pregnant sheep using tracer kinetic techniques. The clearance rate of oestrone for all animals (3·435 ± 0·212 (s.e.m.) 1/min) was significantly greater than that of oestradiol-17β (2·449 ± 0·155 1/min). The mean conversion ratio of oestrone to oestradiol-17β was 23·8±1·6%, and that of oestrone to oestradiol-17α was 17·7 ± 2·5%. The transfer constant of oestrone to oestradiol-17β was estimated to be 17·5 ± 1·6% compared with that of oestradiol-17β to oestrone which was 23·2 ± 2·5%. The production of oestrone increased from values of 0·141 and 0·240 μg/min up to 2 days before parturition, to between 0·660 and 1·881 μg/min during the last 24 h of pregnancy; these values were appreciably greater than those of oestradiol-17β.
During the continuous infusion of [3H]oestrone or [3H]oestradiol-17β and when a steady state had been reached, the uptake by erythrocytes of [3H]oestrone was 22·3%, that of [3H]oestradiol-17β, 6·6%, and that of [3H]oestradiol-17α, 22·0%. In three experiments on one sheep, the uptake of [3H]oestrone across the head was 11–16%.
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SUMMARY
The metabolic clearance rate of oestradiol-17β from whole blood and its conversion to oestrone and oestradiol-17α were measured in pregnant and non-pregnant (cyclic, lactating and anoestrous) sheep using tracer kinetic techniques. The metabolic clearance rate was much the same in sheep in different reproductive states (mean in all animals (±s.e.m.) = 2·449 ± 0·155 1/min). The highest values were reached on days 143–145 of pregnancy (3·287 ± 0·3351/min). The mean conversion ratio of oestradiol-17β to oestrone was 17·0 ± 2·2%, and that of oestradiol-17β to oestradiol-17α was 14·1 ± 1·1%. The production rate of oestradiol-17β increased from 0·007 to 0·103 μg/min up to 3 days before parturition to 0·035–1·257 μg/min during the last 12 h of pregnancy.
During the continuous infusion of [3H]oestradiol-17β and when a steady state had been reached, approximately 20–30% of the radioactivity in whole blood could be extracted with ether. Of this radioactivity more than 90% was attributable to labelled oestradiol-17β, oestrone and oestradiol-17α in jugular blood, though only about 70% could be accounted for as these oestrogens in uterine venous blood.
