Role of Adrenocortical Steroids in the Regulation of Gastric Secretion

Role of Adrenocortical Steroids in the Regulation of Gastric Secretion

Vol. 52, No. 2, Pa rt 1 Printed in U.S.A . GASTROENTEHOLOG)- Copyright © 1967 b y The Williams & Wilkins Co. PROGRESS IN GASTROENTEROLOGY ROLE OF ...

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Vol. 52, No. 2, Pa rt 1 Printed in U.S.A .


Copyright © 1967 b y The Williams & Wilkins Co.



Research, Veterans A dministration CenteT, and Department of Medicine, UCLA Center fO T the Health Sciences, Los Angeles, California

The question of a role for the adrenal glands in the regulation of gastric secretion was raised in the early 1950's with the widespread use of corticosteroids and reports of an increased incidence of peptic ulcer following the administration of these agents. This led to an investigation of the mechanism of ulcer formation and of the possible role of the adrenal cortex in the maintenance of gastric secretory function. A classical method used in endocrinology is the removal of the gland under study and observation of the effect so produced. Following this, replacement therapy is used to ascertain whether the normal state can be restored. However, the adrenal gland has such widespread actions in the organism involving many systems that it is difficult to know whether any effect on the stomach is direct or secondary to some other altered mechanism. It is the purpose of this reviewer to examine critically the evidence relating the adrenal glands with gastric secretion. This can be considered under four headings. Presented at the Symposium of the Gastroenterology Research Group, Annual M eeting of the American Gastroenterological Association, Chicago, Illinois, May 26, 1966. Address requests for reprints to: Dr. A. R. Cooke, Department of Medicine, UCLA Center for the Health Sciences, Los Angeles, California 90024. This work was supported by United States Public H ealth S2rvice Grant AM 8354. The author is greatly indebted to Dr. Morton 1. Grossman for his helpful criticism and encouragement.

1. The effect of adrenalectomy and adrenal hypofunction on acid secretion. 2. The effect of adrenalectomy and replacement therapy on pepsin secretion. 3. Possible mechanisms for altered gastric secretion induced by adrenalectomy. 4. The effect of corticosteroid given to the intact animal-acute and chronic administration.

The Effect of Bilateral Adrenalectomy and Adrenal Hypofunction on Gastric Acid Secretion Bilat eral adrenalectomy reduced gastric acid secretion in the pylorus-ligated rat,1-9 chronic gastric fistula rat,lO and the acute gastric fistula cat.l1 In Pavlov and H eidenhain pouch dogs,12, 13 bilateral adrena lectomy reduced gastric secretion to submaximal histamine stimulation. The maximal acid output in response to histamine was reduced about 60% in dogs with H eidenhain pouches 14 and chronic gastric fistulas (Cooke, Nahrwold, and Grossman, unpublished observations). However, using hog gastrin as a stimulus, m aximal acid output was significantly reduced in dogs with gastric fistulas (Cooke, Nahrwold, and Grossman, unpublished obse1'vations) but was unaltered in dogs with Heidenhain pouches. 15 Chronic administration of SU 4885, an 11 ,a-hydroxylase inhibitor, reduced gastric secretion in dogs. 16 In all animal studies with the exception of the in vitro mouse stomach,17 removal of the adrenals reduced gastric secretion.


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In man, numerous studies in patients with Addison's disease have shown hypochlorhydria using submaximal histamine stimulation or test meals. 18 -23 However, in two studies in which the maximal histamine test (0.04 mg of H.A.P. per kg) was used, it was found that patients with Addison's disease had either achlorhydria, hypochlorhydria, or normal gastric acid secretion. 24 , 25 Although both these studies provide important information regarding acid secretion and mucosal changes in Addison's disease, neither report answers the question of what happens to gastric secretion in untreated patients following adrenalectomy. In a study in patients with Cushing's syndrome, 1 %0 adrenalectomy reduced acid secretion to a gruel meal stimulus. 26 A criticism of this study is that the gruel test meal is a n unreliable test of gastric secretion. Furthermore, of 4 patients examined before and a fter operation, acid secretion was still within the normal range, although at the lower limits. There seems little doubt that the adre; nals are necessary to maintain normal gastric secretion in all animals studied, except the in vitro mouse preparation. The evidence for man is not conclusive. Adrenalectomy involves the loss of the adrenal cortical hormones, cortisol, corticosterone, and aldosterone, as well as the adrenal medullary hormones, epinephrine and norepinephrine. Although the question of the role for the adrenal medulla has not been fully investigated, Tuerkischer and Wertheimer1 found that bilateral adrenal medullectomy in pylorus-ligat ed rats had no effect on gastric secretion. This is in contrast to the findings of Jones and Harkins,7 who showed that adrenal medullecto my produced an effect similar to total adrenalectomy. These findings7 are difficult to reconcile with other evidence concerning the effect of epinephrine and norepinephrine on gastric secretion. These substances have, if anything, an inhibitory effect. 27


Effect of Replacement Therapy in Adrenalectomized Animals

Acute administration of aldosterone to dogs did not alter gastric secretionP D esoxycorticosterone acetate (DOCA) in dogs l3 ,14 or pylorus-ligated rats 1 did not restore acid output to normal. In two studies in pylorus-ligated rats,3, 5 p artial restoration of acid secretion was found. This effect was due to an increase in volume of juice and this may be explained on the basis of overhydration, evidence for which was present in both studies. In the rat and dog, glucocorticoid either completely restored 1, 4, 5, 12, 14, 28, 29 or partially restored 3, 13 gastric acid secretion. In one of these studies3 probably insufficient glucocorticoid was given. Gastric acid secretion in adrenalectomized dogs was restored to normal by glucocorticoids in a period greater than 3 hI' but less than 24 hr.14 In the rat, acid output was restored in 3 days using cortisone acetate. 4 In 2 patients with Addison's disease, sodium chloride, DOCA, and cortisone used in combination altered gastric secretion in response to submaximal histamine stimulation. 22 , 23 In the patient of Stempien and Dagradi,22 only pH was measured and this decreased after treatment. In the patient of Engel,23 free acid (29 units) was found after the patient was treated . Both studies are suggestive of an increase in acid secretion but, since only concentration was measured under conditions of submaximal histamine stimulation, this does not prove that corticosteroids are capable of restoring secretion to normal in patients with Addison's disease. The study of Smith et a1. 24 is of more significance. In 14 patients with Addison's disease treated for years with cortisone and DOCA, 11 were found to have either achlorhydria or hypochlorhydria. Ten of these 11 patients had gastric biopsies performed and 7 of these showed evidence of chronic atropic gastritis or gastric atrophy. The failure of glucocorticoids to restore secretion to normal in these patients may be on a basis of gastric mucosal damage. Three patients


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had normal biopsies in the presence of hypochlorhydria or achlorhydria. It is difficult to explain low acid secretion in the presence of normal gastric mucosa in patients with Addison's disease who are well maintained on corticosteroids. It is possible that to restore acid secretion to normal in Addison's disease requires glucocorticoids in excess of amounts necessary for normal health. The effect of sodium chloride alone has been investigated in a few studies. In the rat, sodium chloride has been shown to have no effect1 or to cause partial restoration,3. 8 again probably on a basis of overhydration. Sigel et al.,12 using pouch dogs, found that 12 g of NaCl per day would restore acid output completely. However, only 48 hr were allowed between suspending cortisone and commencing NaCl, a period insufficient to allow the effects of the glucocorticoid to subside. In a series of animals studied over months, sodium chloride (4 g per day) did not restore acid outpuV 4 (fig. 1). In summary, glucocorticoids are necessary to restore acid secretion in the rat and dog. The evidence for man is not con-

clusive. Sodium chloride or mineralocorticoids exert no effect on gastric acid secretion. Effect of Adrenalectomy and Replacement Therapy on Pepsin Secretion

All studies on the rat (pylorus-ligated and chronic gastric fistula) have shown a decrease in pepsin output following adrenalectomy.1, 6, 8, 10 In the dog it has been reported that bilateral adrenalectomy reduced pepsin output, but the data were insufficient to warrant such a conclusion. 13 In recent studies it has been shown that bilateral adrenalectomy in dogs with Heidenhain pouches or gastric fistulas did not alter pepsin output to any significant degree, even though the maximal acid output was significantly reduced (Cooke, Nahrwold, and Grossman, unpublished data) (fig. 2). In studies using adrenal cortical blocking agents, it was found in the rat that pepsin output was reduced 6 whereas in the dog there was no effect even though acid secretion was significantly reduced. 16 Pepsin secretion was restored to normal in the rat with adrenal cortical extract only,


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FIG. 2. Effect of adrenalectomy (H eidenhain pouch dogs) on acid output, pepsin ooncentration, and output with histamine stimulation. Each line represents 12 experiments in 4 dogs; the vertical bars represent the BE.

in one study,! whereas in another 30 it was found that sodium chloride or glucocorticoid or adrenal cortical extract were all effective. There have been numerous studies by Gray and co-workers measuring uropepsin secretion during glucocorticoid or adrenocorticotropic hormone (ACTH) therapy.31-37 In patients with Addison's disease, it was reported that uropepsin secretion was reduced and could be restored to normal with glucocorticoids. 37 These findings must be viewed in the light of the study of Smith et al.,24 who have shown that gastric atrophy is common in Addison's disease, and of the reports of Hirschowitz et aI.,3S-40 indicating that uropepsin is not a reliable index of gastric pepsin

secretion. Glucocorticoids may act to increase pepsin excretion by a direct action on the kidney.3s, 40 . To summarize, adrenalectomy reduces pepsin secretion in the rat but not in the dog. Glucocorticoids restore pepsin secretion in the rat. In man there have been no studies of the effect of adrenalectomy on pepsin secretion. In Addison's disease uropepsin secretion is reduced, but this in no way proves that gastric pepsin secretion is altered. Possible Mechanisms for Altered Acid and Pepsin Secretion after Adrenalectomy

Is there gastric cellular atrophy? It has been shown that following adrenalectomy



circadian periodicity of surface and mucus neck cells persisted in the rat.41 However, there was a reversal of the normal rhythm. In all studies on the rat 10, 42-45 and one in the dog 46 there has been no evidence of parietal cell degeneration. In the cat47 it was stated that the mucosal weight was less but no histological changes were reported. In Addison's disease two studies 24 ,25 have shown changes ranging from complete normality to gastric atrophy. Changes in the chief cells of the rat have been described,42,43 whereas others could find no change in the volume of gastric mucosa. 44 , 45 In the dog46 no evidence of parietal or chief cell atrophy was found following hypophysectomy even though gastric secretion was significantly reduced. Taking these findings into consideration and despite a significant reduction in acid secretion following adrenalectomy in the rat and dog, one must conclude that there is no evidence of parietal cell atrophy. Furthermore, the evidence in the rat for chief cell degeneration is equivocal despite a significant change in pepsin secretion. Pepsin secretion in the dog is unaltered by adrenalectomy, and cellular changes were not found. In man the changes are difficult to assess. No studies of the effect of adrenalectomy on pepsin secretion have been carried out. It is obvious that the adrenalectomized state in man is not the same as Addison's disease. In adrenalectomy there is a sudden and complete loss of all adrenocortical hormones, whereas in Addison's disease the process is one of a slow temporal reduction of circulating corticosteroids and seldom with complete absence of these hormones. Furthermore, the reported gastric mucosal changes in Addison's disease 24 , 25 are probably due to the development of autoantibodies to stomach and not to lack of circulating corticosteroids.25, 48 Are there metabolic changes? This would seem very likely since the adrenal hormones are involved in metabolic processes. However, there are no studies on metabolic function of gastric mucosa after adrenalectomy. There is indirect evidence to

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show that the fed, unstressed adrenalectomized animal in electrolyte balance has a normal metabolic rate, normal blood sugar, normal liver and muscle glycogen, and a relatively normal growth curve. 49 Is the mucosal barrier defective? It has been shown recently that the gastric mucosa is an effective barrier to the passage of hydrogen ion ;50 about 100 ftEq per 30 min of acid are absorbed from the lumen to the blood in dogs with Heidenhain pouches. l4 , 50 The factor or factors controlling this barrier are unknown. The possibility of one of these factors being corticosteroid was investigated. It was found in dogs with Heidenhain pouches that the amount of instilled acid absorbed from lumen to blood was unaltered by adrenalectomy.14 Thus in the presence of decreased acid secretion the gastric mucosal barrier remained intact. Is there a defective blood supply? There is undoubtedly something wrong with the microcirculation in adrenalectomized animals. They exhibit muscle fatigue sooner than normal animals, but this only occurs in the in vivo situation and not in vitro and is preceded by a marked fall in blood pressure. 51, 52 Thus in vitro muscle receiving its normal nutrients did not fatigue. Furthermore, the small blood vessels of adrenalectomized rats had less tone and did not show spontaneous vasomotion. 53 These changes were restored to normal by topical or systemic adrenocortical extracts. 53 This evidence, together with the work of Dolcini et al.,54 is suggestive that the blood supply to the stomach of the adrenalectomized animal may be defective and thus causes a decrease in gastric secretion. However, until simultaneous measurements of secretion and mucosal blood flow are done in adrenalectomized animals the question of a defective blood supply remains unanswered. In summary, there is no satisfactory explanation for a decrease in gastric secretion following bilateral adrenalectomy. The Effect of Corticosteroids Given to the Intact Animal

Acute administration. An acute effect is

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taken to mean any change in gastric secretion (basal or stimulated) measured for various periods up to 24 hr. Studies have been done in the mouse,17 rat, 55, 56 cat,57 pig, 58 dog,16, 58-62 monkey,63 and man. 40, 45, 61, 64, 65 In the mouse,17 cat,'i7 pig,58 and man 40 , 45 , 61, 64, 65 acute administration of glucocorticoids or ACTH did not alter gastric secretion. In the monkey63 the pH of gastric juice fell after giving ACTH or glucocorticoids. This study has been criticized because the animals were anesthetized, no data as to variation between animals were given, and only pH was measured. Although the study is an old one and is frequently cited, its findings have never been confirmed. In the dog, glucocorticoids or ACTH either have no effecV 6, 58, 60-62 or cause a minor Increase in basal secretion. 59 In the rat, glucocorticoids either decreased 55 or increased gastric acid output. 56 Further studies will have to be done in the rat in order to resolve this question. In summary, acute administration of glucocorticoids or ACTH appears to exert no effect on gastric secretion in man or animals. Chronic administration. This refers to effects on gastric secretion following treatment for periods greater than 24 hr. In the rat, chronic glucocorticoid administration caused no effect on gastric secretion. 4, 5, 56, 66, 67 In the dog there is evidence for an increase in acid and pepsin secretion68 - 79 as well as evidence against. 28 , 58, 61, 80 In the majority of these reports, data were inadequately reported (usually as percentage change of secretion above basal levels which were not given) ,68, 71, 77 or a poor stimulus was used,15, 76, 80 or the 24-hr secretion method was employed. 28 , 58, 61, 69, 7 2, 74 A criticism of the 24-hr collection method is that acid output fluctuates markedly from day to day since such variables as quantity, rapidity, and time of food ingestion are not taken into consideration. The exceptions in the studies referred to previously are the reports of Plainos et al. ,'0, 79 Weinshelbaum et al.,78 and Clarke et aL73 Plainos

et apo, 79 and Weinshelbaum et aU 8 used submaximal histamine stimulation , and only Clarke et al. 73 used maximal histamine stimulation. All three groups reported that chronic glucocorticoid administration increased gastric secretion significantly. In dogs with Heidenhain pouches we found that 50 mg of hydrocortisone per day increased significantly maximal acid and pepsin output in response to histamine and gastrin (Cooke, Nahrwold, and Grossman, unpublished data) (fig. 3). The latent interval to produce an effect was 2 to 3 days, a finding in keeping with a previous report.73 Chronic aldosterone administration to dogs was reported as producing similar effects as glucocorticoids. 73 This finding must await confirmation before acceptance in the light of what is known about mineralocorticoids from other studies. 1, 5, 13, 14 In man, as the dog, there is evidence for 31 , 34, 45, 81-84 and against38, 45, 61, 64, 80, 83, 1600

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FIG. 3. Effect of hydrocortisone on acid output (A) and pepsin output (B) in response to hista-

mine and gastrin. Each point represents the mean maximal output on the day studied for three experiments in 3 dogs. The control studies represent the mean of nine experiments in 3 dogs; the vertical baTS represent the SE.



85-87 an increase in acid and pepsin secretion with chronic administration of ACTH or glucocorticoids. In only three studies 45 , 80, 86 was any attempt made to study patients other than during basal conditions, which are subject to considerable variation. Beck et al.,80 using 12 healthy students, could find no effect of glucocorticoids on submaximal histamine-stimulated acid secretion. Similarly, Ferstl et al.,86 using ACTH, found an actual decrease in acid secretion. Crean45 only has studied acid secretion during corticosteroid administration under the more precise conditions of the maximal histamine test. In preliminary reported data, he found that glucocorticoids increased acid secretion in all of 6 patients whereas this effect was found in only 7 of 14 subjects treated with ACTH, 4 of the 14 actually showing a decreased acid secretion. To summarize, glucocorticoids have no effect on acid secretion in the rat, whereas in the dog acid and pepsin secretions are increased. The question in man is unresolved. What is the mechanism for increased acid and pepsin secretion? In the dog there is some, albeit poor, evidence for an increase in the number of parietal cells corresponding in time to the increase in gastric secretion. n , 88 In man there have been no studies. In the rat one study89 was reported as showing an increase in parietal cell counts. The criticisms of this study are that the method of counting used is subj ect to fallacy since no measurement of total acid-bearing area was undertaken, no concomitant secretory studies were done, and, finally, the work has not been confirm ed by secretory findings of others 4 , 5, 56, 66, 67 or by parietal cell counting. 45 From this survey, this reviewer believes the following observations appear to be warranted. 1. Bilateral adrenalectomy reduces acid secretion in animals. Studies in man are insufficient to warrant any conclusion except to say that Addison's disease is usually associated with hypochlorhydria. 2. Bilateral adrenalectomy reduces pepsin secretion in the rat but not in the dog.

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3. Glucocorticoids but not mineralocorticoids restore acid and pepsin secretions to normal following adrenalectomy. 4. Acute glucocorticoid administration has no effect on acid secretion. 5. Chronic glucocorticoid administration to animals with intact adrenals has no effect in the rat and increases acid and pepsin secretions in the dog. In man the evidence is inconclusive. 6. There is no satisfactory theory to explain the decrease in acid secretion following adrenalectomy. REFERENCES 1. Tuerkischer, E., and E. Wertheimer. 1945.


3. 4.


Adrenalectomy and gastric secretion. J. Endocr. 4: 143-151. Madden, R. J., and H. H. Ramsburg. 1951. Gastric secretion in the adrenalectomized rat. Endocrinology f/J: 82-85. Madden, R. J ., and H. H. Ramsburg. 1951. Adrenalectomy in the Shay rat. Gastroenterology 18: 128--134. Welbourn, R. B., and C. F. Code. 1953. Effects of cortisone and of adrenalectomy on secretion of gastric acid and on occurrence of gastric ulceration in the pylorus-ligated rat. Gastroenterology 23: 356-362. Kyle, J ., and R. B. Welbourn. 1956. Influence of adenohypophysis and the adrenal cortex on gastric secretion in the rat. Brit. J . Surg.

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6. Manrique, J., R. Paredes, J. Arabehety, and S. J. Gray. 1958. Effect of Amphenone on gastric secretory activity. Amer. J. Physiol. 195 : 211-228.

7. Jones, T. W., and H. N. Harkins. 1958. Evaluation of mechanisms involved in gastric acid secretion of pylorus-ligated rats. Gastroent erology 35: 309-311. 8. Hirschowitz, D. I., and W. G. Underhill. 1959. Synthesis and secretion of pepsinogen in the rat; effects of alteration of adrenal activity and of body hydration. Amer. J. Physiol. 196: 837-840.

9. R adecki, T., S. Konturek, and J. Kaulbersz. 1963. Effect of the extirpation of t hyroid, adrenals and gonads on gastric secretion and ulcer formation in rats. Acta Physiol. Pol. 14 : 29-35. 10. Bralow, S. P., S. A. Komarov, and H . Shay. 1964. Effect of total adrenalectomy on gastric secretion in chronic gastric fistula rats. Amer. J. Physiol. 206: 1309-1314. 11. Corral-Saleta, J . M. 1960. Influencia de las

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suprarrenales sobre la secreci6n gastrica. Rev. Esp. Fisiol. 16: 231-239. 12. Sigel, B.,J. G. Bassett, and D. R Cooper. 1956. The effect of cortisone on histamine stimulation of gastric secretion in the adrenalectomized dog. Surg. Forum 7: 362-365. 13. Gilder, H., and F. G . Moody. 1966. Aldosterone effect on canine gastric juice. Proc. Soc. Exp; BioI. Med. 121: 913-918. 14. Cooke, A. R, R M. Preshaw, and M. I. Grossman. 1966. Effect of adrenalectomy and glucocorticoids on the secretion and absorption of hydrogen ion. Gastroenterology 50: 761767. 15. Cooke, A. R, R M. Preshaw, and M. I. Grossman. 1965. Gastric mucosal hydrogen ion

transfer and adrenocorticoids. Clin. R es. 13: 253.

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cortisone upon the stomach: its significance in the normal and in peptic ulcer. Gastroenterology 19: 658-674. Gray, S. J., J. A. Benson, R W. Reifenstein. 1951. Effect of ACTH on gastric secretion. Proc. Soc . Exp. BioI. Med. 78: 338-342. Gray, S. J ., C . G. Ramsey, R W. Reifenstein, and J. A. Benson. 1953 . The significance of hormonal factors in the pathogenesis of peptic ulcer. Gastroenterology 25: 156-172. Gray, S. J., and C. G. Ramsey, 1957. Adrenal influences upon the stomach and the gastric responses to stress. Recent Progr. Hormone Res. 13: 583-617. Gray, S. J. 1959. Present status of endocrine influences upon the stomach and their relationship to peptic ulcer disease. Gastroenterology 37: 412-420. Gray, S. J. 1961. Endocrine influences on the gastrointestinal tract. Amer. J. Dig. Dis. 6:

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sinogen (uropepsin) excretion during ACTH administration and in duodenal ulcer patients. J. Lab. Clin. Med. 50: 209-215. 39. Hirschowitz, B. I. 1957. P epsinogen : its origins, secretion and excretion. Physiol. Rev. 37: 475-511. 40. Hirschowitz, B. I., D. H. Streeten, J. A. London, and H. M. Pollard. 1957. Effects of eight hour intravenous infusions of ACTH and the adrenocortical steroids in normal man. J. Clin. Invest. 36: 1171-1182. 41. Baker, B. L. 1965. Influence of extra gastrointestinal hormones on the stomach, p. 17-30. In J. R Gamble and D . L. Wilbur [eds.],



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