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Am J Physiol Endocrinol Metab 289: E361-E362, 2005; doi:10.1152/classicessays.00033.2005 Free Article
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EDITORIAL FOCUS

ESSAYS ON APS CLASSIC PAPERS

Adrenocortical function, feedback, and alphabet soup

Mary F. Dallman

Department of Physiology University of California San Francisco, San Francisco, California

ABSTRACT

This essay examines the historical significance of an APS classic paper that is freely available online: Ingle DJ. The effects of administering large amounts of cortin on the adrenal cortices of normal and hypophysectomized rats. Am J Physiol 124: 369–371, 1938 (http://ajplegacy.physiology.org/cgi/reprint/124/2/369).

IN THE 1930S, scientists were not wordy. Dwight J. Ingle and Edward C. Kendall published an approximately one-column-long paper (half a page, with data) in Science that concluded: "Our results indicate that the anterior pituitary or some mechanism which controls its activity is sensitive to variation in the amount of cortin in body fluids or to physiologic functions influenced by cortin and that changes in the adrenal are mediated by changes in the output of the adrenotropic principle from the pituitary" (8). Ingle and Kendall (Fig. 1) had previously reported that this might be so through studies of the effects of cortin (adrenocortical extract) on adrenal regeneration. However, Ingle followed up the suggestion provided in the Science paper with an immaculate three-page paper in the American Journal of Physiology that nailed the issue (7).



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  		Fig. 1. Dr. Dwight J. Ingle. (Courtesy, Dept. of Public Relations, University of Chicago)

 
Typical of Ingle's work, the four sets of controls for the two experimental groups were both necessary and sufficient to answer the question. The observation was that treatment of rats with cortin resulted in marked adrenal atrophy; the question was whether the treatment was a consequence of a direct effect of cortin on the adrenals or an indirect effect through modulation of ACTH secretion from the anterior pituitary. Ingle chose to answer the question by treating intact and hypophysectomized rats with large daily doses of cortin and to treat a second group of hypophysectomized rats with both an ACTH preparation and cortin, thus testing whether the effects of cortin were direct or indirect. However, hypophysectomized rats eat less and have small adrenals, so Ingle included a pair-fed intact group to test whether reduced feeding decreased adrenal weight (it did not). The paper includes a table of final body weight and a figure showing scattergrams of the six groups of rats studied. The issue was put to bed: cortin caused adrenal atrophy; injection of ACTH in hypophysectomized rats blocked the cortin-induced adrenal atrophy. Therefore, Ingle appropriately concluded that "the hypothesis that atrophy of the adrenal cortex may be due to restriction of the output of the adrenocorticotropic principle of the anterior lobe of the pituitary is supported by these observations" (7), and a cottage industry in trying to understand further the long-loop negative feedback action(s) of glucocorticoids on function of the hypothalamo-pituitary-adrenal (HPA) axis was born.

This cottage industry persists to the present, with many labs throughout the world in hot pursuit of how, and where, glucocorticoids exert their major inhibitory effects on the HPA axis, and the issue is still not resolved. Many suggest that the feedback actions of glucocorticoids on ACTH secretion are on the hippocampus, where there is such a seductively high concentration of receptors (see, e.g., Refs. 4, 6, 11); others suggest that a major site is at the corticotropin-releasing factor (CRF) neurons in the hypothalamus (see, e.g., Refs. 3 and 5), and still others point to the corticotrope in the anterior pituitary as a major site (see, e.g., Refs. 10 and 12). Agreement is yet to come about on the issue so clearly raised by Ingle in the 1930s.

Ingle and Kendall worked closely together at the Mayo Clinic in the 1930s, and it was a very effective collaboration that continued, between the consummate physiologist and the equally consummate chemist. Kendall was responsible for characterization and synthesis of many adrenal steroids, and in 1950 he shared the Nobel Prize in Physiology or Medicine for his work on adrenal steroids with Tadeus Reichstein at the Pharmaceutical Institute in Basel, Switzerland, and with Philip S. Hench, who demonstrated the powerful effects of treating patients with rheumatoid arthritis, as well as a host of other diseases, with synthetic preparations of cortisone (1). It is because of the work of Kendall and Reichstein that the adrenal steroids are frequently referred to as single letters of the alphabet.

The steroids were isolated from adrenal glands by extraction with organic solvents, the extract was concentrated, and then aliquots were spotted on paper or alumina columns for subsequent chromatographic separation in one or another solvent mixture. Because the mixture of steroids in the extract was separated by chromatography into different bands or fractions of unknown substances, both Kendall and Reichstein labeled their chromatographic spots with letters. Thus, Kendall's Compound B was corticosterone, the major glucocorticoid secreted by the rat. Similarly, Reichstein's Substance S turned out to be 11-deoxycortisol, and Kendall's Compound E was cortisone (11-dehydrocortisol). Kendall's Compound F (or Reichstein's Substance M) was cortisol, the major adrenal glucocorticoid secreted by humans. Both the proper and the familiar names of these adrenal steroids are long, many in the range of 14 letters or so. Therefore, it became common usage to refer to the specific steroid by its chromatographic identification by either Kendall or Reichstein: B, E, F, or S. The clinical (and some basic) literature still uses this shorthand. When an inhibitor of the adrenal enzyme 11{beta}-hydroxylase, such as metyrapone, is used to determine the effects of reduction of negative feedback on ACTH by the active adrenal hormone, it is common to refer to measurement of Compound S (2). Similarly, F is measured in urine (urinary free F) to determine activity in the adrenocortical system. There are letters that have identified enough chromatographic spots to fill the alphabet twice; however, only Compounds B, F, and S are still in some use today. I personally prefer the use of B and F to the other common abbreviation, "cort", which does not distinguish between the two active adrenal glucocorticoids.

Ingle and Kendall had a long and illustrious interaction. When the chromatographic letters had been distinguished as chemical entities and synthesized, Ingle proceeded to test the relative biological efficacy of many different compounds (e.g., Ref. 9). Ingle's work provided the impetus to generations of scientists to study negative feedback regulation in endocrine systems and generally showed how clean experiments should be designed.

FOOTNOTES


Address for reprint requests and other correspondence: M. Dallman, Dept. of Physiology Univ. of California San Francisco, San Francisco, CA 94143-0444 (e-mail: dallman{at}itsa.ucsf.edu)

REFERENCES

  1. _____________. Nobel Lectures, Physiology or Medicine 1942–1962. Amsterdam: Elsevier, 1964.
  2. Berneis K, Staub JJ, Gessler A, Meier A, Girard J, and Muller B. Combined stimulation of adrenocorticotropin and compound-S by single dose metyrapone test as an outpatient procedure to assess hypothalamic-pituitary-adrenal function. J Clin Endocrinol Metab 87: 5470–5475, 2002.[Abstract/Free Full Text]
  3. Di S, Malcher-Lopes R, Halmos KC, and Tasker JG. Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci 23: 4850–4857, 2003.[Abstract/Free Full Text]
  4. Feldman S and Weidenfeld J. Glucocorticoid receptor antagonists in the hippocampus modify the negative feedback following neural stimuli. Brain Res 821: 33–37, 1999.[Medline]
  5. Ginsberg AB, Campeau S, Day HE, and Spencer RL. Acute glucocorticoid pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis hormone secretion and expression of corticotropin-releasing hormone hnRNA but does not affect c-fos mRNA or fos protein expression in the paraventricular nucleus of the hypothalamus. J Neuroendocrinol 15: 1075–1083, 2003.[CrossRef][Medline]
  6. Holsboer F. Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord 62: 77–91, 2001.[CrossRef][ISI][Medline]
  7. Ingle DJ. The effects of administering large amounts of cortin on the adrenal cortices of normal and hypophysectomized rats. Am J Physiol 124: 369–371, 1938.[Free Full Text]
  8. Ingle DJ and Kendall JC. Atrophy of the adrenal cortex of the rat produced by the administration of large amounts of cortin. Science 86: 245, 1938.
  9. Ingle DJ, Nezamis JE, and Morley EH. The comparative value of cortisone, 17-hydroxycorticosterone and adrenal cortex extract given by continuous intravenous injection in sustaining the ability of the adrenalectomized rat to work. Endocrinology 50: 1–4, 1952.[Medline]
  10. Keller-Wood ME and Dallman MF. Corticosteroid inhibition of ACTH secretion. Endocr Rev 5: 1–24, 1984.[Abstract]
  11. McEwen BS, Weiss JM, and Schwartz LS. Retention of corticosterone by cell nuclei from brain regions of adrenalectomized rats. Brain Res 17: 471–482, 1970.[CrossRef][ISI][Medline]
  12. Widmaier EP and Dallman MF. The effects of corticotropin-releasing factor on adrenocorticotropin secretion from perifused pituitaries in vitro: rapid inhibition by glucocorticoids. Endocrinology 115: 2368–2374, 1984.[Abstract]



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This Article
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Right arrow Abstract Freely available
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Right arrow Alert me when this article is cited
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Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
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Right arrow PubMed Citation
Right arrow Articles by Dallman, M. F.

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