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 ratesThe 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 circulatoryA 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.1. Holzbauer, M. and Vogt, M. 1961. Corticosteroids in plasma and
cells of adrenal venous blood. J. Physiol. 157. 137 - 156. ||
2. Holzbauer, M. and Vogt, M. 1966. Investigations into the causes
of the rise in aldosterone secretion during haemorrhage. Parts
I and II. Phil. Trans. R. Soc. London, 250. 243 - 310. ||
3. Holzbauer, M. 1964. The part played by ACTH in determining the
rate of aldosterone secretion during operative stress.
J. Physiol. 172. 138 - 149. ||
4. Holzbauer, M. and Vogt, M. 1964. Observations on slow rhythmic
blood pressure waves (Mayer waves) in the dog. J. Physiol.
172, 5 - 7P. ||
5. Heap, R. B. and Holzbauer, M. 1965. Gas chromatography of
androgens, progesterone and progesterone derivatives in adrenal
venous blood of pigs and dogs. J. Physiol. 183. 11 P. ||
6. Heap, R. B., Holzbauer, M. and Newport, H. M. 1966. Adrenal
secretion rates of C-19 and C-21 steroids before and after
hypophysectomy in the pig and the dog. J. Endocr. 56. 159 - 176. ||
7. Holzbauer, M. and Newport, H. M. 1967. Evidence for the presence
of l6α-hydroxypregn-4-ene-3,2C-dione in adrenal venous blood of
young pigs. J. Physiol. 191. 691 - 697. ||
8. Holzbauer, M. and Newport, H. M. 1968. Secretion of 5P~
hydroxypregn-5-en-20-one (pregnenolone) by the adrenal gland.
Nature, 217, 967 - 968. ||
9. Holzbauer, M. and Newport, H. M. 1968. Quantitative estimation
of 17α-hydroxypregn-4-ene-3, 20-dione (l7αOH-progesterone) in
adrenal venous blood and adrenal glands. J. Physiol. 198,
91 - 102. ||
10. Holzbauer, M. and Newport, H. M. 1969. Adrenal secretion
rates and adrenal tissue concentrations of pregnenolone,
progesterone, 11ßOH-androstenedione and some other steroids
in young pigs and dogs. J. Physiol. 200, 821 - 848. ||
11. Holzbauer, M., Newport, H. K., Birmingham, M. K. and Traikov, H.
1969. Secretion of pregn-4-ene-3,20-dione (progesterone)
in vivo by the adrenal gland of the rat. Nature, 221.
572 - 573. ||
12. Fajer, A. B. and Holzbauer, M. 1968. Pregnenolone, progesterone
and 20-dihydroprogesterone in rat ovarian blood and ovaries
during the oestrous cycle. J. Physiol. 196. 99 - 101P. ||
13. Holzbauer, M, and Newport, H. M. 1967. The effect of stress on
the concentration of 3ß-hydroxypregn-5-en-20-one (pregnenolone)
and pregn-4-ene-3,20-dione (progesterone) in the adrenal gland
of the rat. J. Physiol. 193. 131 - 140. ||
14. Holzbauer, M. and Vogt, M. 1954. The action of chlorpromazine
on diencephalic sympathetic activity and on the release of
adrenocorticotrophic hormone. Br. J. Pharmac. Chemother. 2,
402 - 407. ||
15. Holzbauer, M. and Vogt, M. 1958. The release of corticotrophin
during severe stress in the rat treated with pentobarbitone
and morphine. Acta Endocrinologica 29. 231 - 237. ||
16. Rembeisa, H., Holzbauer, M., Young, P. C. M., Birmingham, M, K.
and Saffran, M, 1967. Metabolism of 17a-methylandrostenediol
and 17ß-methyltestosterone by the rat adrenal gland in vitro.
Endocrinology, 81, 1278 - 128
