G. Virginia Upton

HYPERADRENOCORTICISM AND ACTH-RELEASING FACTOR

The association between a nonendocrine tumor and hyperadrenocorticism was first reported 45 years ago.’ The entity of Cushing’s syndrome was not described until several years later, and the significance of the association was not then apparent. During the subsequent 35-40 years, more than 100 additional cases were reported. The great majority of these were oat cell carcinomas of the lung, malignant thymomas, or islet cell carcinomas of the pancreas (TABLE 1) .2 The striking association of certain histological types of tumors with specific patterns of endocrine abnormalities is most evident in carcinoma of the lung,s in which adrenocortical hyperfunction is associated with oat cell carcinoma, inappropriate antidiuresis with oat cell, and adrenocarcinoma and pseudohyperparathyroidism with epidermoid carcinoma (TABLE 2). In 1962, Liddle and associates demonstrated the presence of ACTH-like activity in the extracts of tumors of patients with Cushing’s syndrome and nonendocrine tumors and coined the term “ectopic ACTH syndrome” to explain the pathogenesis of the disorder.‘ Extensive studies by Liddle’s group and other investigators emphasized the apparent similarity between ectopic ACTH and human pituitary ACTH when comparisons were made of biological activity, chromatographic mobility, and inactivation by physical or chemical procedures. Only minute amounts of ACTH-like activity were found in tumor tissue extracts, and it was assumed, but not proven, that the tumors elaborated minute amounts of ACTH identical in structure to human pituitary ACTH.5 In our labbratory, with methods employed for the isolation of human pituitary ACTH of very high purity, we have been able to isolate tumor peptides with ACTH-like activity that differ in amino acid composition from human pituitary ACTH.6 We also have been able to demonstrate the presence of additional peptides with corticotropin-releasing factor (CRF) -like activity,’ thus suggesting that the ectopic ACTH syndrome may not be due to a single pathological mechanism.

The binding of cortisol by plasma protein

Abstract When plasma cortisol concentrations are less than 30 μg./100 ml., the steroid is tightly bound by protein and cannot be ultrafiltered. When the concentration is raised higher than 40 μg./100 ml., either by addition of exogenous cortisol in vitro or as a result of the effects of adrenocorticotropic hormone (ACTH) or of sickness on the endogenous cortisol concentration, approximately 15% of the steroid is ultrafiltrable. There appears to be no qualitative difference between the binding of exogenous and endogenous steroid at high concentrations. These data seem to indicate that two different types of binding of cortisol occur in human plasma.

Simultaneous Determination of Cortisol and Corticosterone in Human Plasma by Quantitative Paper Chromatography.

Summary and Conclusions A method is presented for measuring Cortisol and corticosterone simultaneously in a single specimen of plasma. The steroids are purified by paper chromatography, eluted and measured by fluorometry. Losses incurred during analytical procedure are compensated by application of an isotope dilution correction. The normal range of corticosterone in human beings is 0 to 5 μtg/100 ml, with a mean of 1.3 ± 2.5 μg/100 ml. The normal range for Cortisol is 4.0 to 17.7 μg/100 ml, with a mean of 10.2 ± 3.6 μg/100 ml.

Absorption of Cortisol from the Colon in Ulcerative Colitis.

Summary Rectal Cortisol has been used in treatment of chronic ulcerative colitis with good results. Following administration of 200 mg of the steroid dissolved in 100 cc of normal saline, there was no significant increase in blood levels of cortisol. This was confirmed by absence in the plasma cortisol fraction of any appreciable radioactivity following instillation of cortisol-4-C14. By implication, our data suggest that the good clinical results obtained were probably the result of a local effect of the cortisol on the rectal mucosa.

Purification of Porcine and Human ACTH

Homogeneous ACTH from porcine and human sources can now be prepared in moderate quantities because suitable starting material is available, and fractionation on large Sephadex and carboxymethyl cellulose columns is readily reproducible. The purified peptides are necessary for immunologic, metabolic and chemical studies. To prepare porcine adrenocorticotropic hormone, the starting material is the fraction made for clinical use by carrying the extraction of whole pituitaries through an oxycellulose adsorption step. For human adrenocorticotropic hormone, by-products from preparations of human growth hormone are used. Detailed procedures for purifying adrenocorticotropic hormone isolated from human and porcine sources are described below.