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Title: Studies on the in vivo secretion and metabolism of the steroid hormones of the adrenal cortex
Author: Holzbauer-Sharman, Margarethe
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1969
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This thesis consists of publications describing experiments in which the secretion of steroid hormones by the adrenal cortex was studied. The venous effluent from the adrenal glands of several mammalian species was collected under anaesthesia. Chemical methods were developed which allow the simultaneous qualitative and quantitative analysis of most steroid hormones synthesized by the adrenal cortex. These methods were applied to blood and tissue extracts. Because of the observation (paper 1) that a large proportion of the steroids in the blood is loosely associated with blood cells, whole blood samples were extracted instead of plasma alone. The experiments have given information on the type of steroids secreted by the adrenal cortex and on factors which influence the rate at which they are secreted. One group of papers is concerned with the control of aldosterone secretion in the dog (papers 2, J and 4). A detailed study of the factors which cause a rise in aldosterone secretion following acute haemorrhage (paper 2) led to the conclusion, that acute blood loss stimulates the release of hormones from the pituitary gland and the kidney. These hormones in turn cause increased aldosterone secretion. In this respect the two organs can replace each other. In dogs which prior to the experiment had been maintained for long periods of time on either very low or very high dietary sodium intake it was usually not possible to observe the aldosterone rise after blood loss. The aldosterone stimulating substance released from the pituitary gland is in all probability ACTH. This is strongly supported by a quantitative study in which aldosterone secretion was measured in the same dog before and after hypophysectomy and during subsequent infusions of ACTH (paper 3). The increase in aldosterone secretion was found to depend on the dose of ACTH, provided aldosterone secretion was not maximally stimulated by factors not of pituitary origin. In the same experiments information was obtained on the rate at which ACTH was secreted during anaesthesia and operative stress, by comparing glucocorticoid secretion rates before hypophysectomy with those after hypophysectomy, when ACTH was infused at different rates The condition of the circulation before and after haemorrhage was found to be important for the ability of a dog to respond to blood loss with a rise in aldosterone secretion. The occurrence of a certain type of blood pressure waves (Mayer waves) is indicative of circulatory A second group of papers (5 - 13) is concerned with a class of corticosteroids which has so far not been studied in a systematic and quantitative manner, mainly because they are only secreted in small quantities and methods for their estimation had not been available. The papers describe the development and adaptation of paper and gaschromatographic techniques for the purpose of a qualitative and quantitative study of these steroids. Pregnenolone, progesterone, 17αOH-progesterone, 11ßOH-progesterone and the three so called adrenal androgens androstenedione, adrenosterone and 11 SOH-androstenedione were consistently found to be present in the extracts of adrenal venous blood of dogs and young pigs in concentrations similar to or higher than those of aldosterone. Hypophysectomy caused a fall in the secretion of these steroids, similar to that of the glucocorticoids (papers 6, 8 and 9) but their secretion did not cease completely, indicating that these steroids are not only secreted by an overactive gland under conditions of stress "but also under resting conditions. In addition to the above steroids, l6αOH-progesterone was found to be secreted by the adrenal gland of the young pig). Certain experimental conditions modified the secretion of pregnenolone and 11ßOH-androstenedione in a different way from that of other steroids (paper 10). Studies of this type may eventually help to explain certain clinical signs of adrenal deficiency and overactivity which cannot fully be attributed to the lack or excess of glucocorticoids or aldosterone. The quantities of progesterone secreted by the adrenal gland of the pig (papers 5, 6 and 10) and the rat (paper 11) can be of the same order as those secreted by the ovaries of the same species (paper 12) under similar experimental conditions. A comparison between the rates at which steroids are secreted with the concentrations in which they are present in the adrenal tissue of one and the same animal provides some information on the rates of steroid synthesis in vivo (papers 9 and 10). The quantity of a given steroid present in the adrenal of a pig or dog was found to correspond to the amount secreted within 0.5 to five minutes. Pregnenolone and progesterone were exceptions to this rule. Assuming that these two steroids are the most important precursors of all the steroids secreted by the adrenal, it can be calculated, that the amounts at which they are present in the adrenal will be utilized within 1-5 minutes. Any stimulus leading to an increased secretion of adrenal steroids must therefore effect an increase in the rate at which pregnenolone is formed. In accordance with this, it was found that in the rat (paper 13) stress does not only cause a rise in the adrenal concentration of corticosterone but also of pregnenolone and progesterone. The papers 10, 14 and 15 contain information on the possible use of drugs to prevent the release of ACTH caused by anaesthesia and the operative procedures required for adrenal vein cannulation. Chlorpromazine and morphine were not able to overcome this severe stress in the rat (papers 14 and 15). In dogs anaesthetised with sodium pentobarbitone in which the left adrenal vein had been cannulated, a-ethyltryptamine had an effect on steroid secretion similar to that of hypophysectomy. However it lacked this effect in dogs anaesthetised with chloralose and in dogs which had been eviscerated(paper 10). The last paper (16) deals with the mechanism by which 17α-methylandrostenediol inhibits corticosterone production by the rat adrenal.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (D.Sc.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available