II. Own investigation: Studies on the metabolism of 4‐C 14 ‐cortisol in newborn infants

Summary Some general aspects of the degradation of cortisol and the conjugation of cortisol metabolites are outlined. Special reference is made to the glucuronyl transferase enzyme system, which is relatively deficient in newborns. The results of some important studies on the cortisol metabolism in new‐born infants are summarized. It is concluded that the available data in the literature, although somewhat conflicting, indicate that the pathways of cortisol metabolism in newborn infants differ from those in adults in important qualitative, as well as quantitative, interrelationships. The deficient glucuronyl transferase activity in the foetal and neonatal period seems to play a significant role in this difference, but a possible inhibition in the reduction of the Δ 4 ‐3‐ketone in Ring A has also to be taken into consideration. However, the newborn infants seem to have at their disposal alternative pathways of cortisol metabolism which, at least in part, may compensate for these restrictions. Thus transformation of increased amounts of cortisol to 6 β‐hydroxy‐cortisol, and probably to other highly hydroxylated metabolites, assumes a more important role, and the existence of other compensatory mechanisms, as yet undefined, seems probable. Following intravenous administration of a tracer dose of 4‐C 14 ‐cortisol the urinary excretion of radioactive cortisol metabolities was studied in 3 normal adult subjects, 7 newborn full‐term infants, 8 new‐born premature infants, and 13 newborn infants of diabetic mothers. The principles of an extraction procedure have been outlined. By means of this procedure the urinary cortisol metabolites were separated into the following 5 fractions: the free low‐polar fraction, the free high‐polar fraction, the low‐polar glucuronoside fraction, the high‐polar glucuronoside fraction, and the sulphate‐conjugated fraction. Statistical analyses of duplicate determinations indicated a reasonable degree of precision of the method. I t was found that the urinary excretion of radioactivity was delayed in the neonates, and most pronounced in the premature infants, in comparison with the adults. The excretion pattern of the newborn infants of diabetic mothers was rather similar to that found in normal full‐term infants. It was demonstrated that the initial lag in the excretion of urinary cortisol metabolites in the newborn was most marked in the output of the glucuronoside fractions. All newborn infants studied excreted more in the free high‐polar fraction than the adults. There was no correlation between the magnitude of this fraction and the gestational age of the infants. The premature infants excreted significantly more in the free low‐polar fraction than the full‐term infants, and there was furthermore an inverse correlation between the magnitude of this fraction and the gestational age of the infants. The excretion in the free low‐polar fraction in infants of diabetic mothers exceeded that which would be expected from their gestational age. The low‐polar glucuronoside fraction accounted for a much lower percentage in all infants studied than in adults. The premature infants excreted significantly less in this fraction than the full‐term infants. There was a positive correlation between the magnitude of the low‐polar glucuronoside fraction and the gestational age of the infants. Furthermore, an inverse correlation was found between the amounts of cortisol metabolites excreted in this fraction and the maximum serum bilirubin level during the neonatal period. The infants of diabetic mothers excreted less in the low‐polar glucuronoside fraction than would be expected from their gestational age. About 50 per cent of the excreted radioactivity in the newborns was unaccounted for. There was no obvious relationship between the severity of the mothers' diabetes, or the degree of ‘Cushingoid’ appearance of their infants at birth, and the magnitude of the different fractions of cortisol metabolites. The explanation of the decreased excretion rate of cortisol metabolites and of the neonatal pattern of cortisol metabolism might presumably lie in immaturity in renal function as well as in the enzyme systems involved in the degradation of cortisol and the conjugation of cortisol metabolites. The present study seems to indicate a connection between the relative deficiency of the glucuronyl transferase enzyme system in newborns and their decreased excretion of glucurono side‐conjugated metabolites of cortisol. This restriction seems to be related to maturity. The newborn infant seems to have at its disposal alternative pathways of cortisol metabolism with an increased ability to form high‐polar derivatives of cortisol. The extent to which these pathways are utilized seems to be unrelated to maturity. The characteristic features of prematurity with regard to the urinary excretion of cortisol metabolites; the increased free low‐polar fraction and the decreased low‐polar glucuronoside fraction were both present in the infants of diabetic mothers, and even more pronounced than would be expected from their gestational age. It seems possible that the increased liability of the infants of diabetic mothers to develop severe jaundice in the neonatal period might be explained on the basis of a derangement in the glucuronic acid conjugating system disproportional to their size and gestational age. The relatively high proportion of urinary cortisol metabolites which remains unextractable in the urine emphasized the necessity of caution in interpreting the adreno‐cortical function in newborns on the basis of determinations of steroids excreted in the urine.