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S. Mulay
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S. Solomon
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Administration of a dose of 45 mg streptozotocin/kg on day 2 of gestation produced a diabetic state in pregnant rats and was associated with fetal hyperinsulinaemia. Although there was no evidence of fetal macrosomia, the ratio of fetal liver and lung weight to body weight was greater in fetuses of diabetic rats, suggesting an increase in the size of these organs relative to the body weight.

Maternal and fetal plasma corticosterone levels of diabetic rats between 19 and 22 days of gestation was significantly lower than the corresponding control values. Maternal plasma progesterone levels of diabetic rats were lower than controls on days 19 and 20 of gestation, but higher than controls on day 21 of gestation. The absence of pregnancy-related changes in maternal and fetal plasma corticosterone levels and maternal progesterone levels in diabetic rats suggest that adrenocortical function as well as ovarian and/or placental function may be impaired, which may in turn be related to the observed delay in parturition of approximately 18 h as well as to the low survival rate of the pups.

There was a small increase in the cytoplasmic glucocorticoid receptor concentration in the lung but not in the liver of fetuses of diabetic mothers when compared with fetuses of controls, suggesting that the increased receptor concentration may be a compensatory mechanism to overcome the effect of decreased corticosterone levels and increased insulin levels in the fetuses of diabetic rats.

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S. Mulay
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A. Philip
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S. Solomon
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The influence of maternal diabetes on fetal development was studied in rats made diabetic by administration of streptozotocin on day 2 of gestation as well as in genetically diabetic BB Wistar rats. A dose of 65 mg streptozotocin/kg produced severe diabetes with plasma glucose levels of approximately 36 mmol/l, this was associated with fetal growth retardation but not fetal hyperinsulinaemia. In contrast, a smaller dose of streptozotocin (45 mg/kg) produced moderate diabetes with plasma glucose levels of approximately 20 mmol/l and was associated with fetal hyperinsulinaemia but only a marginal effect on fetal size. In both groups of diabetic animals, maternal body weight gain was decreased, maternal plasma insulin levels were low and fetal glucose levels were similar. In a small group of genetically diabetic BB rats on insulin therapy the fetuses were macrosomic and hyperinsulinaemic. The specific binding of 125I-labelled insulin to partially purified liver and lung membranes of fetuses of both groups of streptozotocin-induced diabetic rats was significantly lower than the binding to membranes from fetuses of control animals. The specific binding of 125I-labelled insulin to fetal liver and lung membranes from the diabetic BB Wistar rats also appeared to be reduced when compared to tissues from controls. Decreased insulin receptors in fetal lung and liver of diabetic rats suggest a role for insulin in the development of these organs during the fetal and neonatal period.

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J. T. BAKER
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S. SOLOMON
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A comparison of the renal response to extracellular fluid volume expansion (5% body weight) was made between 25 normal and 25 chronically hypophysectomized rats. The extracellular fluid compartments averaged 25 ± 1% of body weight in both groups during control, fasted conditions. Extracellular fluid volume increased to 33 ± 1% in hypophysectomized and 34 ± 2% in normal rats during expansion, based on body weight. In addition, filtration fraction was similar in both normal and hypophysectomized rats during control (0·29 ± 0·03 and 0·26 ± 0·02 respectively) and infusion of Ringer–Locke solution (0·24 ± 0·05 and 0·27 ± 0·05 respectively). Thus our results cannot be explained by differences in the degree of expansion or failure to increase filtration in proportion to plasma flow. During infusion of isotonic Ringer–Locke solution, fractional water and sodium excretion both averaged 5·1% in normal rats and only 1·3% and 0·82% respectively in hypophysectomized rats. The ratio of single nephron to whole kidney filtration rate failed to increase as much in hypophysectomized compared with normal rats. Significant increases of fractional volume excretion occurred in both groups by the end of the accessible portion of the proximal tubule. However, fractional water reabsorption was depressed significantly more in normal (mean = 37%) than in hypophysectomized rats (mean = 19%). Fractional water reabsorption in distal tubules was similar in both groups during expansion. Arterial pressure was lower in hypophysectomized rats under control conditions, but showed similar changes during expansion compared with normal rats. Passage time decreased significantly in all groups after Ringer–Locke infusion, but remained prolonged in hypophysectomized rats in proximal and distal tubules. It is concluded that chronic hypophysectomy results in a less efficient renal excretion of volume and sodium chloride load. This inefficiency appears to be related in part to (1) failure of the proximal tubule to depress water reabsorption to a level equivalent to normal rats, and (2) failure to re-distribute flow to outer cortical glomeruli following extracellular fluid volume expansion in hypophysectomized rats.

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J. P. GEORGE
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S. SOLOMON
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The uptake and metabolism of glutamine, production of ammonia and consumption of O2 were studied in kidney slices isolated from mature, gonadectomized and newborn male and female rats in the presence of 0·05, 0·5, 2 and 5 mm-glutamine. Slices isolated from mature intact female rats showed significantly greater conversion of glutamine into CO2 and NH3 without any change in the total uptake of glutamine when compared with all other experimental groups. No difference in O2 consumption was found between mature male and female animals. Ovariectomy reduced glutamine metabolism, NH3 production and O2 consumption without any effect on the total uptake of glutamine. In contrast, castration did not significantly affect glutamine metabolism and production of NH3 but did reduce O2 consumption. Newborn (20- to 21-day-old) rats showed no sex-dependent differences in glutamine uptake and metabolism, production of NH3 and consumption of O2, but values for all these parameters were lower in kidney slices from newborn animals than in kidney slices from mature, intact or gonadectomized male and female rats. It is concluded that in female rats, metabolism of glutamine and production of NH3 may be influenced by ovarian sex hormones.

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S. Mulay
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D. R. Varma
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S. Solomon
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The influence of dietary protein deficiency on maternal plasma corticosterone and progesterone levels as well as on maternal and fetal liver and lung cytoplasmic glucocorti-coid receptors has been studied in Sprague–Dawley rats during the last 3 days of gestation. Plasma corticosterone levels of control but not protein-deficient rats increased on days 20 and 21 of gestation; corticosterone levels of protein-deficient rats decreased on day 21 of gestation. Maternal adrenalectomy caused only a moderate decrease in corticosterone levels in both groups of pregnant rats. Fetal corticosterone levels of the two groups of rats were similar. Progesterone levels were consistently lower in protein-deficient than in control animals from day 20 of gestation until 2–12 h after parturition. There were no differences in the binding of [3H]dexamethasone to liver cytosol of non-pregnant control and protein-deficient rats. However, receptor levels were lower in pregnant controls than in pregnant protein-deficient rats. Maternal protein deficiency led to an increase in fetal liver glucocorticoid receptor levels but exerted no significant effect on receptor levels in fetal lung. It is suggested that lower levels of plasma corticosterone and progesterone and high levels of liver glucocorticoid receptors in protein-deficient rats might be related to some of the adverse consequences of maternal malnutrition on fetal development.

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B. S. MISANKO
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Y. S. PARK
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S. SOLOMON
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Recent work on kidneys from hypophysectomized (hypox) rats has shown atrophy of the proximal tubules with no effects on the other parts of the nephron. We carried out experiments to determine whether the reduction of p-aminohippurate (PAH) is consistent with structural changes in the proximal tubule of hypophysectomized rats. Initial velocities of PAH uptake by renal cortical slices were found to be constant over 30 min of incubation at concentrations of PAH up to 0·5 mmol/l for both control and hypox animals. Using kinetic analysis, it was found that both maximal velocity, V max, and the Michaelis constant, K m, were reduced in hypox animals, the relative reduction being similar for both parameters. Comparison between high Na (100 mmol/l) and low Na (6 mmol/l) media indicated that in both control and hypox rats, V max was significantly lower in low Na medium than in high Na medium, whereas K m was not changed. Efflux of PAH from pre-loaded tissue also showed a reduction in hypox animals. These results may indicate that hypophysectomy alters the capacity of PAH transport in renal cortical slices by (1) reducing the effective transport area or sites, and (2) by changing carrier–substrate affinity.

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K. W. Kan
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R. L. Cruess
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B. I. Posner
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H. J. Guyda
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S. Solomon
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ABSTRACT

In order to assess which hormones may exert direct effects on skeletal growth at the epiphysial growth plate, the specific binding of hormones to the epiphysial cartilage of growing dogs and rabbits was studied. Membrane fractions obtained by centrifugation of homogenates prepared from dog and rabbit growth plate cartilage at 600, 15 000 and 105 000 g showed significant specific binding of serum insulin-like activity and insulin. Binding of growth hormone and prolactin by the three membrane fractions was negligible. Saturable binding sites for triiodothyronine could be demonstrated in nuclei from the dog growth plate. Nuclear binding showed an apparent K d of 11 ±3·6 nmol/l and a maximum binding capacity of 4·1 ± 1·6 pmol/mg DNA, a level comparable to dog liver. Using a viable chondrocyte suspension prepared from dog epiphysial cartilage, specific steroid binding in the cells could be demonstrated for [3H]dexamethasone but not 17α-methyltrienolone, oestradiol-17β or 1α,25-di-hydroxycholecalciferol. Scatchard analysis of dexamethasone binding showed high affinity binding sites having a K d of 1·2 ± 0·35 nmol/l and a capacity of 1700 sites/cell, and a low affinity binding with a K d of 109 ± 57 nmol/l and a capacity of 24 000 sites/cell. Steroid competition for the specific binding showed the following sequence of affinity: dexamethasone > corticosterone > 11-deoxycortisol > testosterone > oestradiol-17β. Although all of the hormones examined except prolactin have well-established physiological effects on skeletal growth, our present results suggest that some of the hormonal effects observed in intact animals are secondary and do not involve receptor–hormone interaction in cartilage as such.

J. Endocr. (1984) 103, 125–131

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W. LING
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J. R. T. COUTTS
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M. C. MACNAUGHTON
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S. SOLOMON
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SUMMARY

Labelled 17α-hydroxyprogesterone was injected into the umbilical vein of each of two male previable human foetuses at the time of laparotomy. The umbilical circulation remained intact for 3 min after which time the tissues of the foetuses, placentae and cords were removed, extracted and the labelled unconjugated metabolites formed were identified. The mid-pregnancy human foetus has a high capacity for metabolizing 17α-hydroxyprogesterone, forming corticosteroids, C-19 steroids and a variety of reduced and hydroxylated metabolites. Androstenedione and testosterone were isolated from both the foetal adrenals and testes but the older of the two foetuses studied contributed in major part to this synthesis. All the foetal tissues examined showed a remarkable capacity to metabolize 17α-hydroxyprogesterone.

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W. LING
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J. R. T. COUTTS
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M. C. MACNAUGHTON
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S. SOLOMON
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SUMMARY

After injection of [4-14C]17α-hydroxyprogesterone into the umbilical vein of two male human foetuses at mid-pregnancy a number of steroid conjugates were isolated from the foetal adrenals, liver, intestines and residual tissues, confirming the capacity of the human foetus to conjugate an extensive range of steroid substrates. The conjugated steroids isolated were 17α-hydroxypregnanolone sulphate (liver, intestine), 3β,17α-dihydroxy-5α-pregnan-20-one sulphate (residue), pregnanetriol sulphate (liver, residue), cortisol sulphate (adrenal), pregnanetriol glucosiduronate (liver, residue) and 17α-hydroxypregnanolone glucosiduronate (liver).

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