ESTROGENS AND GASTRIC SECRETION

Transcription

1 GASTROENTEROLOGY Copyright 1968 by The Williams & Wilkins Co Vol. 54. No.5 Printed in U.S. A. ESTROGENS AND GASTRIC SECRETION HERBERT J. KAUFMANN, M.D., AND HOWARD M. SPIRO, M.D. Section of Gastroenterology, Yale University School of Medicine, New Haven, Connecticut Sex, pregnancy, and the menopause all affect the course of peptic ulcer l - 9 and estrogens have been shown to hasten their healing. lo 11 In view of this, it would be useful to know whether estrogens change gastric secretion and, accordingly, we investigated their effect on gastric secretory activity in peptic ulcer patients and normal monkeys. Methods The augmented histamine test was carried out in the standard manner.12 Results were expressed in terms of basal acid output and maximal acid output, which was taken to be twice the value of the two highest consecutive I5-min samples after histamine. Pepsin determinations using a hemoglobin substrate were also done13: a pepsin unit is the colorimetric equivalent of 1 meq of tyrosine. Animal studies. Eight Macacca mulatta monkeys (7 female and 1 chosen in error, male) weighing 3.8 to 4.7 kg were fasted and placed in special restraining boxes. Two base line gastric analyses were carried out before the administration of 1.25 mg of conjugated equine estrogen intramuscularly daily. Augmented histamine and insulin tests were repeated at weekly intervals for 4 weeks. Follow-up studies were done 1 and 6 weeks after the end of therapy. Augmented histamine tests were performed in the same manner as in patients except that 30-min aliquots were used and the total hour's response was reported. Insulin hypoglycemia was induced b y the administration of 2.5 units of crystalline insulin per kg of Received August 24, Accepted January 5, Address requests for reprints to: Dr. Howard M. Spiro, Gastroenterology Section, Yale University School of Medicine, 333 Cedar Street, Xew Haven, Connecticut We are indebted to Nathan Kase, M.D., of the Department of Gynecology and Obstetrics for his help in examining the patients and for his advice, and to the Ayerst Company for their gift o f P ermarin. 913 body weight. All gastric analyses a fter insulin were carried out for 2 hr. Human studies. Eight patients, 3 with gastric ulcer and 5 with duodenal ulcer, had not responded well to a medical regimen. Four subjects were postmenopausal women (1 with gastric ulcer and 3 with duodenal ulcers) and 4 were sexually inactive men (2 with gastric ulcers and 2 with duodenal ulcers). All women had pelvic and breast examinations by a gynecologist before the study and all subjects were told the nature of the medication, the women being informed of possible breast swelling and vaginal bleeding, the men of gynecomastia. A plausible placebo seemed unrealistic in view of the nature of the side effects. After base line augmented histamine tests were carried out, each patient took conj ugated equine estrogens (Premarin) 1.25 mg twice daily orally for 3 months. Gastric analyses were carried out at approximately 1, 2, 4, 8, and 12 weeks after treatment was sta rted and again 1 month after treatment was stopped. Since no assessment of clinical response was intended, ali patients continued on the usual ulcer regimen of antacids; no anticholinergics were given. One woman terminated treatment at 2 months because of profuse vaginal bleeding. At least six augmented histamine tests were carried out on each patient who completed the course. Four other subjects, 2 m en and 2 women, ali with duodenal ulcer, underwent a total of 10 studies but did not complete the protocol and were thus excluded from the results. The results were tabulated by determining the mean and standard deviation for each group of subjects in each phase of the protocol, i.e., base line, "on t reatment," and "post-treatment." Student's t-test was used to assess significance. Results The results are presented in tabular form. No significant differences were observed save for a rise in pepsin in the post-treatment phase in the patients. This is a rti fac-

2 TABLE 1. Gastric secretion in patients before, during, and after estrogen treatment Patients Age Sex Ulcera Basal acid I Stimu.lated Basal I St i m u l Basal t e d acid I Stimu.lated Basal I S it mu l t e Basal d acid I Stimu.lated Basal I S t ui l m t d e acld pepsin pepsm acid pepsin pepsm acid pepsin pepsin meq/h' /000 U/ hr meq/ iz, 1000 U/hr meq/h' 1000 U/llr O. T. 45 F D T. c. 50 F D M.M. 75 F G R.A. 59 F ]) A.A. 81 M G F. H. 69 M G V. B. 52 M D L. H. 58 M D Mean ± SD ± 1.9 ± 13.8 ± 4.1 ± 5.5 ± 1.8 ± 12.8 ±4.4 ± 11.0 ± 3.9 ± 12.9 ± 6.8 ± 4.8 b D, duodenal; G, gastnc. b I. = , P < 0.02 relative to base libe. See text. <.0... ;; p.. 8 ""

3 May 1968 ESTROGENS AND GASTRIC SECRETION 91.5 TABLE 2. Gastric acid in monkeys before, during, and after estrogen treatment Monkeys Basal I Histaminc- Insulinstimulated stimulated stimulated stimulated stimulated stimulated q ' meij/ ilr meq/2 hr meg/ltr meq/ 2 ilr meq/ Ilr ",Eq/2 ilr 1" Mean ±SD ± 0.14 ± 0.53 ± 0.53 ± 0.08 ± 0.28 ± 0.53 ± 0.11 ± 0.36 ± 0.73 " All monkeys but t his one were females. TABLE 3. Gastric pepsin in monkeys before, during, and after estrogen treatment Monkeys Basal I Histamine- Insulinstimulated stimulated stimulated stimulated stimulated stimulated 1000 U/hr 1000 U/2 ilr 1000 U/hr 1000 U/2 ilr 1000 U/ hr 1000 Uj2 ilr Mean ± SD ± 0.7 ± 1.2 ± 3.0 ± 0.3 ± 1.3 ± 1.9 ± 0.5 ± 0.25 ± 2.6 tual because of the inclusion of L. H., a hypersecretor who had no base line pepsin determination. Discussion Crean reviewed the relations between peptic ulcer and gastric secretion, sex, body size, and estrogens in ; there have been few significant studies since then. H, 15 Of all of the species studied, only in the cat does the administration of estrogens cause a definite decrease in acid secretion After this study was completed, the work of Parbhoo and Johnston became available. 25 They showed no significant change in acid or peptic response to histamine after a short course of estrogens in human subjects. Truelove's controlled, double blind study showed a striking improvement in duodenal ulcer healing after diethylstilbesterol treatment. 10 It can be argued, however, that a study using estrogens with their easily recognizable pharmacological effects cannot be truly double blind, that radiographic evidence alone i unreliable as a criterion for healing of a duodenal ulcer, and that the low rate of healing in the control group (only 10% of the ulcers healed in 6 months) suggested that the population at risk was atypical. In a re-

4 916 KAUFMANN AND SPIRO Vol. 54, No.5 cent study, Connell and his associates were unable to duplicate Truelove's results. 26 The study by Doll et al. of gastric ulcers relies on percentage healing based on X-ray examination.l1 While this is probably the best available way of assessing healing in a gastric ulcer, small differences in the radiographic technique can result in considerable change in the measured size of the crater and quantitative significance should not be assigned to such measurements. In our study, all of the gastric ulcers healed completely radiographically (although one returned later). Duodenal ulcer disease was evaluated by symptoms and no improvement was noted that could not be attributed to antacids, frequent visits to a physician, or the natural course of the disease. Control patients were not studied for the reason already mentioned, i.e., the obvious pharmacological effects of estrogens. Also, the base line study served as the appropriate control for the test periods in each individual. We have no way, therefore, of ruling out a placebo effect. Our data failed to demonstrate that a significant change in acid or pepsin secretion follows the administration of large doses of estrogen in man or monkeys. There was, however, a fall in acid secretion of less than statistical significance in 7 of the 8 patients. If estrogens heal ulcers-and we are not certain that they do-it may be the result of a change in secretion but we have not observed one. Summary The gastric secretory response III patients and monkeys was studied before, during, and after treatment with estrogens. No significant decrease in acid or pepsin secretion could be demonstrated, although a s uggestion of a decrease in acid secretion was noted. This does not, by itself, explain the alleged benefits of estrogens on the course of peptic disease and neither does it explain some of the well recognized sex differences in peptic disease and acid secretion. REFERENCES 1. Clark, D. H Peptic ulcer m women. Brit. Med. J. 1: MacKay, C Perforated peptic ulcer in the west of Scotland: a survey of 5,343 cases during Brit. Med. J.1: Doll, R., and F. A. Jones Occupational factors in the etiology of gastric and duodenal ulcers. Med. Res. Counc. Spec. Rep. (London) 276: Winkelstein, A A possible relationship between the ductless glands secreting the sex hormones and peptic ulcer. J. Mount Sinai Hosp. N. Y. 7: Sandweiss, D. J., H. C. Saltzstein, and A. A. Farbman The relation of sex hormones to peptic ulcer. Amer. J. Dig. Dis. 6: Crean, G. P The endocrine system and the stomach. Vitamins Hormones (N. Y.) 21: McDonald, I Gastric activity during the menstrual cycle. Gastroenterology 30: Clark, D. H., and H. I. Tankel Gastric acid and plasma histaminase during pregnancy. Lancet 2: Spiro, H. M., R. D. Schwartz, and M. L. Pilot Peptic ulcer in pregnancy : a serial study of gastric secretion during pregnancy. Amer. J. Dig. Dis. (New Series) 4: Truelove, S. C Stilbesterol, phenobarbitone and diet in chronic duodenal ulcer. Brit. Med. J. 2 : Doll, R., I. D. Hill, and C. F. Hutton Treatment of gastric ulcer with carbenoxolone sodium and estrogens. Gut 6: K ay, A. W Effect of large doses of histamine on gastric secretion of HCI. Brit. Med. J. 2: Anson, M. L The estimation of pepsin, trypsin, papain and cathepsin with hemoglobin. J. Gen. Physiol. 22 : Vakel, B. J., nd a A. M. Mulekar Studies with the maximal histamine test. Gut 7: Baron, J. H Peptic ulcer, gastric secretion and body build. Gut 5: Ojha, K. N., and D. R. Wood The inhibitory effects of stilbesterol on gastric secretion in cats. Brit. J. Pharmacol. 5: McCarthy, J. D., S. O. Evans, and L. R. Dragstedt Gastric secretion in dogs during pregnancy and lactation. Gastroenterology 27:

5 May 1968 ESTROGENS AND GASTRIC SECRETION Clark, D. H Gastric secretion in dogs during pregnancy and lactation. Scot. Med. J. 12: Hartiala, K. J., A. Kassinen, and H. Sautarinen The beneficial effects of estrogens on experimental cinchophen ulcer. Ann. Med. Exp. Fenn. 312: Mylire, E Regeneration of fundi mucosa in rats: effects of estrone and castration. Arch. Path. (Chicago) 82: Ghosh, M. N Inhibition of acid gastric secretion in the rat by chorionic gonadotropin. J. Physiol. (London) 147: Kahlson, G., B. Lilja, and S. E. Svensson Physiological protection against gastric ulceration during pregnancy and lactation in the rat. Lancet 2: Fell, B. F., K. A. Smith, and R. M. Campbell Hypertrophic and hyperplastic changes in the alimentary canal of the lactating rat. J. Path. Bact. 85: Shelesnyak, M. C Histamine releasing activity of natural estrogens. Proc. Soc. Exp. BioI. Med. 100: Parbhoo, S. P., and 1. D. A. Johnston Effects of oestrogens and progestogens on gastric secretion in patients with duodenal ulcer. Gut 7: Connell, A. M., J. Fletcher, J. Howel Jones, M. J. S. Langman, J. E. Leonard Jones, and F. Pygott Oestrogens and highprotein and high-carbohydrate diets in the treatment of duodenal ulcer (abstr.). Gut 7: 717.