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N. DESHPANDE
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V. JENSEN
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R. D. BULBROOK
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T. W. DOOUSS
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It has been postulated that the increased rate of corticosteroid formation in the adrenal gland after corticotrophin stimulation is due to an increase in the rate of formation of NADPH or an increase in the availability of a corticosteroid precursor (Haynes & Berthet, 1957; Koritz & Peron, 1958). It has also been shown that adrenal tissue has a high level of glucose 6-phosphate dehydrogenase which generates NADPH (Kelly, Nielson, Johnson & Vestling, 1955). In this communication we would like to present evidence that in the human adrenal gland, exogenous NADPH stimulates cortisol synthesis in vivo.

The patients were all cases of advanced breast cancer with widespread metastases undergoing bilateral oophorectomy and adrenalectomy. In nine of them 2 μc of [7α-3H]pregnenolone was injected via the inferior phrenic artery and the adrenal venous blood was collected for 12 min. after the injection. In four patients, 2 μc of radioactive pregnenolone

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V. JENSEN
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N. DESHPANDE
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R. D. BULBROOK
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T. W. DOOUSS
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SUMMARY

The production rate of cortisol in patients with early or advanced breast cancer was compared with that of controls of comparable age. The miscible pool of this hormone was raised in advanced breast-cancer patients due to a higher production rate. The plasma clearance of cortisol remained unaffected, resulting in a higher titre of cortisol (both total and unbound) in advanced breast-cancer patients. There was no significant difference in the production rate between the early breast-cancer cases and controls.

The binding of cortisol to transcortin was studied in all cases. The amount of unbound cortisol was raised in advanced breast-cancer cases. There was a significant correlation between both total and unbound cortisol and the production rate of this hormone. The latter correlation suggests that there is no abnormality in the hepatic extraction of cortisol in these patients.

The metabolic clearance rate was found to be of the order of the blood flow through the liver when unbound cortisol was used for its estimation, showing that it is the unbound cortisol which is removed by the liver.

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V. JENSEN
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N. DESHPANDE
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R. D. BULBROOK
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T. W. DOOUSS
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SUMMARY

The distribution of cortisol in patients with early or advanced breast cancer and in controls was studied, using a two-compartment model for analysis. The patients with advanced breast cancer had significantly raised pool sizes. There were no significant differences in the ratio of two pools found for patients and controls. This suggests that there are no abnormalities in the transfer processes.

There was a significant correlation between the exit rate from the intravascular pool and the production rate of cortisol, showing that there is no major extrahepatic metabolism of this hormone in both controls and in breast-cancer patients.

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T. W. DOOUSS
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S. J. M. SKINNER
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R. A. F. COUCH
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SUMMARY

The role of pregnenolone sulphate in adrenal steroid biosynthesis and the ability of the human adrenal gland to synthesize and secrete dehydroepiandrosterone (DHA) and dehydroepiandrosterone sulphate (DHA sulphate) was investigated. The presence of pregnenolone sulphate and DHA sulphate was demonstrated by measuring their concentrations in human adrenal tissue. Pregnenolone sulphate was metabolized in vitro mainly to free steroids, including DHA and cortisol, as well as directly to DHA sulphate in some cases. Similar results were obtained upon perfusion of the adrenal gland in situ with [14C]pregnenolone and [3H]pregnenolone sulphate as the substrates and isolating the metabolites from the adrenal venous blood. Dehydroepiandrosterone sulphate was derived mainly from the sulphation of free DHA. The hydrolysis of DHA sulphate did not appear to make a significant contribution to the amounts of DHA synthesized under these conditions.

The adrenal secretion of DHA and DHA sulphate by eight patients undergoing adrenalectomy was determined by measuring the concentrations of these compounds in samples of adrenal and peripheral venous blood taken simultaneously. In one patient secretion of DHA and DHA sulphate was equivalent whilst in the remainder there was much greater secretion of DHA.

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N. DESHPANDE
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VIBEKE JENSEN
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PAMELA CARSON
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R. D. BULBROOK
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T. W. DOOUSS
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SUMMARY

A variety of 14C and 3H-labelled steroids have been perfused through the human adrenal gland in situ and their metabolic products isolated from adrenal venous blood.

Progesterone, dehydroepiandrosterone and cortisol were isolated after infusion of [3H]pregnenolone; 17α-hydroxyprogesterone, dehydroepiandrosterone and cortisol after infusion of [3H]17α-hydroxypregnenolone and [14C]progesterone; androstenedione and cortisol after infusion of [3H]17α-hydroxyprogesterone and [14C]dehydroepiandrosterone; and 11β-hydroxyandrostenedione after infusion of [3H]androstenedione and [14C]cortisol.

From a consideration of the incorporation of radioactivity into the metabolic products, the3H: 14C ratios and the tissue pool sizes it was concluded that the major biosynthetic pathway to cortisol in the human adrenal glands was: pregnenolone→ 17α-hydroxypregnenolone → cortisol. Progesterone was not an important intermediary.

Androstenedione was mainly formed by way of 17α-hydroxypregnenolone → 17α-hydroxyprogesterone → androstenedione. 11β-Hydroxyandrostenedione was formed mainly from cortisol and only a minor amount came from the hydroxylation of androstenedione.

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