Factors affecting alternate pathways of corticosteroid excretion: Possible catabolite repression phenomena in man

By employing a method of sequential extraction of β-glucuronidase hydrolyzed urine it was possible to quantitate the excretion of “less polar” 17-OH, 20, 21-ketols (tetrahydrocortisol and tetrahydrocortisone) and of polar 17-OH, 20, 21-ketols. In normal subjects the excretion of the less polar fraction exceeds the polar fraction by a 2 1 ratio. In a patient with a recent infarction of a pituitary tumor and subsequent removal of the tumor, the urinary excretion pattern was found to be abnormal, with a greater excretion of polar 17-OH, 20, 21-ketols and essentially zero levels of the less polar 17-OH, 20, 21-ketols. While the patient was maintained on replacement dosages of dexamethasone, intermittent measured doses of cortisol were also found to lead to the urinary excretion of more 17-OH, 20, 21-ketols in the polar fraction than in the less-polar fraction. After the patient was given an infusion of glucose and a small amount of insulin it was found that the excretion pattern after ingestion of cortisol became essentially normal. The change was due to a 63 per cent decrease in the polar steroid pathway and a 23 per cent increase in the less-polar steroid pathway. On substitution of daily cortisol for replacement it was found that the excretion pattern was essentially normal. The alternate pathways described are dependent on two different enzyme systems, the pathway to the “less-polar” steroids is dependent on reduction of the Δ 4, 3-ketone structure by a hepatic Δ 4, 5 hydrogenase and a 3α hydrogenase. The formation of the polar metabolites is dependent on certain hepatic microsomal hydroxylases. The glucose effect and the effect of maintenance doses of cortisol on these alternate pathways are discussed in terms of enzyme induction and repression. The possibility that the glucose effect noted here is an example of the “catabolite repression” phenomena affecting corticosteroid metabolism is considered.