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It is now well recognized that fasting rats are more suitable than fat-fed rats for the determination of the ketogenic activity of extracts of endocrine organs [Shipley & Long, 1938; Black, Collip & Thomson, 1934; Gray, 1938]. Shipley & Long found that measurements of the increases in ketonaemia were more consistent than those of increases in ketonuria in such investigations.
The experiments described here deal with modifications and improvements in the mode of assay previously described [Gray, 1938] and with the application of such improved methods to the determination of ketogenic potency of material prepared by ammonium sulphate fractionation of extracts of the anterior lobes of ox pituitaries.
In view of the findings of Shipley & Long [1938] that the ketone bodies are threshold substances, a number of assays were checked by using the method described by these workers. In addition, a number of experiments were performed in which the
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It is now recognized that quantitative and qualitative measurements of urinary neutral 17-ketosteroids may be of clinical significance in the diagnosis of certain pituitary and adrenal disorders, but whereas there is much information concerning the normal values in adults, the normal range of excretion in childhood (Table 1) is less accurately known. While the figures obtained by Nathanson, Towne & Aub [1941] are appreciably higher than those of Talbot, Butler & MacLachlan [1940], the more recent figures of Hain [1947] agree with those of Talbot. The present investigation describes the results obtained in a series of normal children within the age group 2–12 years.
Callow & Crooke [1944] suggested that dehydroisoandrosterone was excreted in greatly increased amounts in cases of adrenal cortical tumour and considered that the presence of an abnormally high proportion of this substance in the urine might be of fundamental diagnostic value. Methods for the quantitative isolation
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SUMMARY
The major metabolic pathways of cortisol have been studied in detail after injection of a tracer dose of [4-14C]cortisol in two patients with rheumatoid arthritis and in one with disseminated lupus erythematosus. Results are also presented from preliminary experiments in two other patients with rheumatoid arthritis.
The rates of cortisol secretion by the adrenals of all the patients studied were within the normal range and the kinetics of cortisol metabolism were also normal. No abnormalities were found in either the proportions of cortisol, cortisone and 6β-hydroxycortisol in the urinary fraction containing the unconjugated steroids or in that of tetrahydrocortisol, allo-tetrahydrocortisol, tetrahydrocortisone, cortols, cortolones, 11β-hydroxyaetiocholanolone, 11β-hydroxyandrosterone and 11-oxoaetiocholanolone in the fraction released by hydrolysis of the urinary steroid conjugates.
The excretion of 6β-hydroxycortisol in a group of patients with rheumatoid arthritis was not significantly greater than that in a similar group of normal subjects in whom the upper limit of the range was higher than values previously reported.
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SUMMARY
The major metabolic pathways of cortisol in a patient with sarcoidosis have been studied after intravenous injection of a tracer dose of [4-14C]cortisol. Results from some preliminary experiments in four other patients are also presented. The effects of large doses of cortisol on its metabolism were also studied.
In all the patients studied the adrenal secretion rate of cortisol was in the low normal range. The rate of disappearance of radioactivity from the plasma fractions containing the unconjugated steroids was normal before cortisol therapy but slower than normal during therapy. During therapy there was a significant decrease in the total urinary radioactivity.
In the one patient in whom detailed studies were made, an unusually large proportion of the urinary metabolites was in the unconjugated fraction in which the amount of 6β-hydroxycortisol was greater than normal. Apart from an increased ratio of 11β-hydroxy- to their corresponding 11-oxo-metabolites there was no essential difference in the pattern of excretion of the metabolites in this patient during therapy. In this patient only 65% of the injected radioactivity was excreted in urine after 48 hr., whereas the other patients excreted a normal percentage of the injected radioactivity during this period.
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The metabolism of [1,2-3H] 17α-methyltestosterone (MeT) has been studied in adult human subjects, most of whom had cancer of the breast.
The rates of disappearance of MeT from plasma and of the appearance of metabolites of MeT in plasma have been measured after intravenous injection of [1,2-3H]MeT. In addition, the rate of appearance of [1,2-3H]MeT and of metabolites of MeT in urine and in faeces has been measured after intravenous injection of [1,2-3H]MeT and in urine after oral administration of the steroid. The results show that MeT is metabolized more slowly than testosterone.
Identification of metabolites of MeT which were isolated from the urine of patients to whom this steroid was administered has been attempted. Three compounds, 17α-methyl-5β-androstane-3α,17β-diol (tetrahydro-MeT), 17α-methyl-5α-androstane-3α,17β-diol (allotetrahydro-MeT) and unchanged MeT have been identified, three other compounds have been partially characterized and several others have been isolated. The most abundant metabolites of MeT are hydroxylated compounds reduced in ring A.
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To facilitate a study of the metabolism of 17α-methyltestosterone (MeT), [1,2-3H] MeT and four unlabelled derivatives of MeT were prepared. This report describes the preparation of these compounds.
[1,2-3 H]17α-Methyltestosterone. This was prepared by partial tritiation (at the Radiochemical Centre, Amersham, Bucks.) of 17α-methyl-17β-hydroxy-androst-1,4-dien-3-one (obtained from Ciba Laboratories, Horsham, Sussex). A hundred mg. of the steroid was dissolved in 5 ml. dioxan and shaken for 5 hr. at 22° in 12 ml. of a tritium-hydrogen mixture (5 c) in the presence of 50 mg. 10 % palladium on charcoal. Eighty mg. of steroid were recovered with an average specific activity of 18 mc/mg. [1,2-3H]MeT was subsequently isolated in a 10–15 % yield by paper chromatography of portions of the tritiated material in the cyclohexane: formamide system (Savard, 1953) and then in the A system of Bush (Bush, 1952).
[1,2-3H]MeT thus obtained
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SUMMARY
The binding of cortisol to plasma proteins at room temperature (22–25° c) and 37° c has been studied by equilibrium dialysis against 0·9% NaCl and by gel filtration of the dialysed plasma. The rate of dissociation of the cortisol-transcortin complex during gel filtration of plasma from both normal and oestrogen-treated subjects is a rapid process. The difference in the percentage of cortisol bound as determined by the two methods cannot, therefore, give an accurate measurement of the binding due to albumin.
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SUMMARY
The metabolism of [3H]betamethasone has been studied in normal subjects and in patients receiving high therapeutic doses of the steroid. About 70% of the dose was excreted in the urine in 48 hr.; 15–30% of the dose was found in the unconjugated fraction. Six metabolites as well as unchanged betamethasone were isolated and identified by paper chromatography using reference compounds prepared from [3H]betamethasone. The transformations were: oxidation of the 11β-hydroxyl group, hydroxylation at the 6β-position, reduction of the carbonyl group at C-20 and removal of the side chain to give 17-oxosteroids.
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1. The reducing method of Talbot, Saltzman, Wixom & Wolfe [1945], and the formaldehyde method of Corcoran & Page [1948], as well as a modification of that of Daughaday, Jaffe & Williams [1948] for the estimation of urinary corticosteroids, have been critically examined.
2. A study has been made of the distribution of reducing material, of formaldehydogenic material and of reducing and Δ4-3-ketosteroids, in the various fractions obtained during the various purification procedures applied to the crude CHCl3 extract.
3. Caustic soda washing does not remove significant quantities of the steroids investigated, although non-steroid reducing and uncharacterized formaldehydogenic material is removed.
4. The water fraction of the benzene-water partition contains all the reducing and Δ4-3-ketosteroids so far detected in urine.
5. The formaldehydogenic method of Corcoran & Page gives slightly higher results than the modified method of Daughaday et al.
6. The acid hydrolysis curves obtained with the Talbot method resembled those described by Paterson, Cox & Marrian [1950], but no regular form of hydrolysis curve was obtained when either formaldehydogenic method was used.
7. A comparison of normal values obtained by the authors using the chemical and paper chromatography techniques revealed that the formaldehydogenic methods estimate a very high proportion of uncharacterized material, whereas results by the reducing method of Talbot et al. approximate relatively closely to those obtained by semiquantitative paper chromatography.
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SUMMARY
The α-ketolic steroid R6, previously described by de Courcy, Bush, Gray & Lunnon [1953], has been identified as tetrahydrocorticosterone. The structures of X6 and some other αβ-unsaturated ketones appearing on chromatograms of urine extracts and giving the Bush soda fluorescence reaction are discussed. Four of these compounds are of exogenous origin and follow the ingestion of citrus fruits.
