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K Hardy and S Spanos

There is increasing evidence that even before implantation, human development is regulated by embryonically and maternally derived growth factors. Studies in other mammalian species have shown that growth factors and their receptors are expressed by the preimplantation embryo and the reproductive tract. Furthermore, a number of growth factors have been shown to affect rate of embryo development, the proportion of embryos developing to the blastocyst stage, blastocyst cell number, metabolism and apoptosis. Growth factor ligands and receptors are also expressed in human embryos and the maternal reproductive tract, and supplementation of culture medium with exogenous growth factors affects cell fate, development and metabolism of human embryos in vitro. Autocrine, paracrine and endocrine pathways that may operate within the embryo and between the embryo and the reproductive tract before implantation are proposed.

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Arthur Shulkes, Patricia Chick and K. J. Hardy

In the sheep fetus, plasma levels of gastrin are raised above adult levels from 2 weeks before birth. This observation initiated the present study on the maternal and fetal secretion rate, metabolism and placental transfer of gastrin. The experiments were performed on conscious pregnant ewes with chronically cannulated fetuses and on newborn lambs. Metabolic clearance rate (MCR), production rate (PR) and placental transfer of gastrin were measured by alternate steady-state infusion of gastrin into the mother and fetus. Plasma levels of gastrin were measured by radioimmunoassay.

Metabolic clearance rate was similar in the pregnant and non-pregnant ewe (8·4± 1·1 (s.e.m.) and 9·0±1·4 ml/min per kg) respectively. However, fetal MCR was significantly increased. Term was 145 days. Metabolic clearance rate was 15·5 ± 1·7 at 110–125 days of gestation, 25·6 ± 2·9 at 126–135 days, 29·7 ± 4·9 at 136–145 days and remained raised in the first 2 weeks post partum.

Gastrin did not cross the placenta in either direction. Placental destruction of gastrin was not responsible for the increased fetal MCR as umbilical artery and umbilical vein levels were not significantly different during fetal gastrin infusion. Furthermore, MCR remained raised in the newborn lambs. Gastrin PR was significantly increased at all ages.

The results showed that the previously reported fetal hypergastrinaemia is from fetal sources and is not a result of immaturity of clearance mechanisms. In fact, fetal MCR was significantly increased. The increased fetal plasma gastrin levels are due to an increased rate of production from the fetus.

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Plasma cortisol and corticosterone were separated by Sephadex LH-20 chromatography. The high concentration of plasma cortisol immediately after birth in the guinea-pig coincided with the decline in 125I-labelled polyvinyl pyrrolidone (PVP) uptake (closure) between 48 and 72 h. Similarly, in the rabbit, plasma cortisol concentration was increasing at the time of closure, 18–21 days after birth. These results suggest that there is a correlation between the time when the concentration of the main plasma adrenocortical steroid rises and the time when the neonatal small intestine ceases to take up PVP.

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K. G. Braslis, A. Shulkes, D. R. Fletcher and K. J. Hardy


Calcitonin gene-related peptide (CGRP) is a product of the calcitonin gene with a widespread distribution in neural tissue of the brain, gut and perivascular nerves. Infusion of CGRP produces multiple biological effects, but the physiological significance of these findings will be influenced by the sites and rates of CGRP metabolism.

The metabolic clearance rate and half-life of disappearance of human CGRP were estimated in conscious sheep after infusing CGRP at 1 or 5 pmol/kg per min to steady-state conditions. The particular organs involved in the clearance of CGRP were assessed by measuring the inflow and outflow concentrations across the liver, gut, kidney, lung and brain.

The metabolic clearance rate at steady state was 22·6 ± 2·1 (s.e.m.) and 15·0±1·7 ml/kg per min for the 1 and 5 pmol/kg per min doses respectively. The half-life of disappearance was bi-exponential: 3·6±0·3 min for the first phase and 13·6±1·0 min for the second phase. High-pressure liquid chromatography of plasma at equilibrium revealed only a single peak coeluting with CGRP(1–37): no immunoreactive metabolites were detected. These pharmacokinetic values are intermediate between that of a neurotransmitter and a hormone and are therefore consistent for a peptide with both circulatory and neurotransmitter modes of action. The kidney, with an arterial–renal vein gradient of 14%, and the liver, with a portal– hepatic vein gradient of 25%, were the major organs involved in the clearance of CGRP. The specific organ clearance, however, accounted for only one-third of the whole body metabolic clearance rate of CGRP, suggesting that other more generalized degradative systems are involved, such as endothelial-bound enzymes of blood vessels. This information on clearance and organ-specific metabolism should form a basis for evaluating the physiological roles and modes of action of CGRP.

J. Endocr. (1988) 118,25–31

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B. Quérat, K. Nahoul, A. Hardy, Y. A. Fontaine and J. Leloup-Hâtey


Intact and hypophysectomized freshwater (FW) silver eels were transferred to tanks of FW or artificial sea water (SW; salinity = 0·60 osmol/l) which were simultaneously renewed twice a week. Fish were killed 2 months after transfer and plasma was assayed for ovarian steroids.

In all fish, 5α-androstane-3β,17β-diol was present, while 5α-dihydrotestosterone and 5α-androstane-3α,17β-diol were undetectable.

In intact FW eels, plasma levels of testosterone, 5α-androstane-3β,17β-diol and oestradiol-17β were approximately 0·15 nmol/l. In intact SW eels, no change in plasma levels of testosterone and 5α-androstane-3β,17β-diol was found, whereas the concentration of oestradiol-17β was increased significantly (P<0·01), indicating stimulation of aromatase activity.

In hypophysectomized compared with intact FW fish, plasma levels of testosterone and 5α-androstane-3β,17β-diol were decreased (P<0·05) and there was a slight but significant (P<0·01) augmentation of the plasma concentration of oestradiol-17β which may have involved the removal of pituitary-dependent inhibition of aromatase activity, possibly by 5α-reduced compounds.

In hypophysectomized compared with intact SW fish, plasma levels of testosterone, 5α-androstane-3β,17β-diol and oestradiol-17β were decreased (P<0·05); in the case of oestradiol-17β, this may have reflected the diminished ovarian synthesis of testosterone, its precursor. The plasma level of oestradiol-17β was, however, higher in SW than in FW fish, even in hypophysectomized eels. This suggests that extra-pituitary mechanisms mediate, at least partly, the effects of transfer to SW on aromatase activity.

J. Endocr. (1987) 114, 289–294

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The villous epithelial cells of the terminal part of the rat small intestine readily absorb maternal antibodies and certain other macromolecules up to the 18th day after birth. Between 18 and 21 days, however, these cells are progressively replaced by more mature cells, and the uptake of macromolecules declines to zero (Clarke & Hardy, 1969a, b). This process has been termed 'closure'.

Closure can be induced at least 9 days before the normal time by the administration of deoxycorticosterone acetate or cortisone acetate (Halliday, 1959). Furthermore, bilateral adrenalectomy at 15–18 days after birth has been shown to delay the time of closure (Daniels & Hardy, 1971). These results suggest that the functional development of the adrenal cortex may determine the maturation of the small intestine with respect to its ability to absorb macromolecules.

In order to investigate further the possible role of the adrenal gland in the mechanism of

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* Department of Physiology, University of Melbourne, Parkville, Victoria 3052, Australia, † Department of Surgery, Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia, and ‡ Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Victoria 3052, Australia

(Received 19 October 1977)

Aldosterone is present in the peripheral blood of ovine foetuses from at least 60 days until term at 147 ± 5 days (Wintour, Brown, Denton, Hardy, McDougall, Oddie & Whipp, 1975). To determine the biological significance of this steroid in the foetus, infusions of aldosterone were made into foetuses bearing chronic vascular and bladder cannulae and the urinary sodium: potassium Na+: K+) ratio was measured before, during and after infusion. Silastic cannulae (0·76 mm internal diameter, 1·65 mm outer diameter) were placed 6–8 cm into the left carotid arteries and right jugular veins of seven ovine foetuses between 86 and 120 days of gestation and a

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D. P. Hennessy, J. P. Coghlan, K. J. Hardy, B. A. Scoggins and E. M. Wintour

The blood clearance rate (BCR) of cortisol was measured in non-pregnant ewes and in pregnant ewes and their intact or bilaterally adrenalectomized fetuses. In pregnant sheep the placental transfer of cortisol in both directions was established. The BCR of cortisol in the non-pregnant sheep was 51·7±4·9 (s.e.m.)1/h (n = 36) or 1·151/h per kg body weight. This was lower than that in the pregnant ewe (97–143 days of gestation) of 76·9±4·21/h (n = 9) or 1·851/h per kg.

In the intact fetus the BCR was 8·2±0·261/h (n = 10) over the same period of gestation. The percentage of the maternal production rate of cortisol transferred to the fetus was 1·4±0·11% (n = 9) and the placental transfer from fetus to mother was 19·5±1·5% (n = 8). The BCR in pregnant ewes bearing bilaterally adrenalectomized fetuses was not significantly different from that of mothers of intact fetuses (58·4±7·71/h; n = 6). The BCR of adrenalectomized fetuses was 8·4±1·371/h (n = 8). The placental transfer of cortisol from mother to fetus was sufficient to account for all the cortisol measured in adrenalectomized fetuses and in intact fetuses of 100–121 days of gestation. However, it accounted for only 37% of the cortisol measured in fetuses of 122–135 days of gestation and 12% or less in fetuses older than 136 days of gestation.

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To determine the percentage of the maternal secretion of aldosterone which crosses the placenta the blood clearance rate (BCR) of aldosterone was measured in pregnant sheep and in chronically cannulated fetuses by the constant infusion of [3H]aldosterone alternately into the maternal and fetal compartments. When equilibrium had been reached the concentration of [3H]aldosterone was measured in both maternal and fetal compartments. Aldosterone BCR in eight pregnant ewes was 98 ± 5 (s.e.m.) litres/h which was not significantly different from that of ten non-pregnant ewes at 95 ± 5 litres/h. The BCR of aldosterone in seven fetuses was 24 ± 2 litres/h. A small percentage (4·4 ± 0·3; n = 7) of the maternal production rate was transferred to the fetus, whilst 29 ± 4% (n = 8) of the fetal production rate was transferred to the maternal compartment.

When aldosterone was measured in maternal and fetal blood samples collected simultaneously from sodium-replete sheep more than 80% of the aldosterone in fetal blood was of fetal origin if the actual fetal concentration of aldosterone was greater than 1·5 ng/dl.

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Metoclopramide (10 mg i.v. injection followed by 10 mg/h i.v. for 2 h) caused a transient rise in blood concentrations of aldosterone in sodium-replete and sodium-depleted sheep. Infusion of metoclopramide into the adrenal artery of sheep with an autotransplanted adrenal gland, at a rate to give a similar concentration of metoclopramide at the adrenal cell level (calculated from rate of infusion and adrenal blood flow), resulted in no alteration in aldosterone secretion rate in either sodium-replete or sodium-depleted animals, even though intravenous metoclopramide caused transient stimulation of aldosterone secretion in the same sheep when sodium replete.

Dopamine administered either into the adrenal arterial blood supply or intravenously had no significant effect on aldosterone secretion and did not reverse the stimulatory effects of angiotensin II on aldosterone secretion in the adrenal transplant.

The data do not support the suggestion that direct dopaminergic elements play a tonic inhibitory role in aldosterone secretion. It is possible that the agonist effect of metoclopramide on aldosterone secretion may occur by some non-dopaminergic mechanism and it is tempting to speculate that the effect is centrally mediated.