1. Urinary 17-oxosteroid conjugates were measured by gas-liquid chromatography in five patients with hereditary coproporphyria. 2. Three patients were in an acute attack and showed significantly increased excretion of sulphate or glucuronide conjugates of aetiocholanolone. There was increased excretion of several other related steroids but no consistent pattern was apparent. 3. In the two patients in remission, excretion of urinary 17-oxosteroids was not increased. 4. The ratio of total urinary aetiocholanolone to androsterone (5β:5α) was found to be significantly elevated for the three patients in an acute attack. Serial measurements were made in two of these patients and showed a highly significant linear correlation between this ratio and the urinary content of δ-aminolaevulic acid and porphobilinogen. 5. These observations suggest the involvement of the 17-oxosteroids, especially aetiocholanolone, in the pathogenesis of hereditary coproporphyria.
1. Gas—liquid-chromatographic methods were established to measure the concentrations of the main 17-oxosteroid conjugates in plasma and the urinary excretion of the main metabolites of these steroids in human subjects. These steroids were assayed in the urine of thirty-eight normal males and thirty-seven normal females and in the plasma of fifty-eight normal males and thirty-nine normal females; the data were used as controls for the further investigations of the amounts of these steroids in thirty-four patients with acute intermittent porphyria. 2. The seven patients examined in acute attack of this disease had significantly increased excretions of the urinary sulphate and/or glucuronide conjugates of dehydroepiandrosterone (3β-hydroxyandrost-5-en-17-one) and aetiocholanolone (3α-hydroxy-5β-androstan-17-one). There were increases in the concentration of dehydroepiandrosterone sulphate in the plasma of four patients (in an attack) in whom the plasma 17-oxosteroids were determined. Lesser increases in the plasma concentrations of several other 17-oxosteroid sulphates were observed but no consistent pattern was apparent. Similar abnormalities of urine and plasma 17-oxosteroids were observed in sixteen of the patients in remission. These increased excretions and increased plasma concentrations of certain 17-oxosteroid conjugates were associated with increased excretion of porphyrins and porphyrin precursors in the urine. 3. The urinary ratio of aetiocholanolone to androsterone (3α-hydroxy-5α-androstan-17-one) was significantly greater than normal in patients with acute intermittent porphyria. In one patient studied over several weeks in an attack the concentrations of δ-aminolaevulic acid and porphobilinogen in urine correlated significantly with the steroid ratio. 4. Dexamethasone treatment of one patient in an attack resulted in significant reductions in excretion of the individual 17-oxosteroids and of porphyrins and porphyrin precursors. This was accompanied by a noticeable improvement in his clinical condition. 5. A series of three C 18 , twelve C 19 and five C 21 steroids were given intraperitoneally to rats. Only dehydroepiandrosterone, 17-hydroxypregnenolone (3β-hydroxypreg-5-en-17-ol-20-one), androstenedione (androst-4-ene-3,17-dione), androstenediol (androst-4-ene-3β,17β-diol) and aetiocholanolone caused significant elevations of hepatic δ-aminolaevulic acid synthetase. Although dehydroepiandrosterone and its sulphate were active in this system, the acetate and glucuronide of this steroid were not. Elevations of δ-aminolaevulic acid synthetase activity caused by dehydroepiandrosterone could be abolished by the antibiotics cycloheximide and actinomycin D. 6. These observations suggest the involvement of the 17-oxosteroids, especially dehydroepiandrosterone and aetiocholanolone, in the pathogenesis and control of acute intermittent porphyria.