The Effects of Female Sex Steroids on Gastric Secretory Responses of Rat Following Traumatic Brain Injury

Document Type: Original Article


1 Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran

2 Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran

3 Kerman University of Medical Sciences, Kerman, Iran

4 Neuroscience and Physiology Research Centers, Kerman University of Medical Sciences, Kerman, Iran


Gastric ulceration is induced by various forms of stress like surgery, ischemia and trauma. The female sex has more resistance to stress and the gastrointestinal lesions happen fewer than male sex. The purpose of this study was to evaluate the role of estradiol and progesterone on the gastric acid and pepsin levels following traumatic brain injury (TBI) induction.
Materials and Methods
Diffuse TBI was induced by Marmarou method in female rats. Rats randomly assigned into 9 groups: intact, OVX (ovarectomized rat), Sham+OVX, TBI (intact rats under TBI), TBI+OVX (ovarectomized rats under TBI) and  treated  OVX  rats  with  vehicle  (sesame  oil),  E2  (estradiol),  P4  (progesterone)  or  E2+P4 combination. The acid content and pepsin levels of each gastric washout sample were measured 5 days after the TBI induction.
There was no significant difference in gastric acid output between groups either after TBI induction or after treatment with E2 or P4 or E2+P4. Gastric pepsin levels were increased in Sham+OVX, TBI (P< 0.001) and TBI+OVX (P< 0.05) compared to intact group. Gastric pepsin levels were significantly lower in E2 and E2+ P4 treated rats than vehicle treated group (P< 0.01). P4 treatment increased gastric pepsin level compared to TBI+OVX group (P< 0.05) and this increment was higher than rats that were treated with the E2 and E2+P4 (P< 0.01).
These results suggest that protective effect of estradiol and E2+P4 combination against mucosal damage after TBI, might be mediated by inhibition of pepsin secretion.


1. Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma 2006; 60:S3-11.

2. Rutland-Brown W, Langlois JA, Thomas KE, Xi YL. Incidence of traumatic brain injury in the United States, 2003. J Head Trauma Rehabil 2006; 21:544–548.

3. Hukkelhoven CW, Steyerberg EW, Rampen AJ, Farace E, Habbema JD, Marshall LF, et al. Patient age and outcome following severe traumatic brain injury: an analysis of 5600 patients. J Neurosurg 2003; 99:666-673.

4. Angele MK, Ayala A, Monfils BA, Cioffi WG, Bland KI, Chaudry IH. Testosterone and/or low estradiol: normally required but harmful immunologically for males after trauma-hemorrhage. J Trauma 1998; 44:78–85.

5. Jackson MD, Davidoff G. Gastroparesis following traumatic brain injury and response to metoclopramide therapy. Arch Phys Med Rehabil 1989; 70:553-555.

6. Pilitsis JG, Rengachary SS. Complications of head injury. Neurol Res 2001; 23:227-236.

7. Norton JA, Ott LG, McClain C, Adams L, Dempsey RJ, Haack D, et al. Intolerance to enteral feeding in the brain injured patient. J Neurosurg 1988; 68:62-66.

8. Kao CH, ChangLai SP, Chieng PU, Yen TC. Gastric emptying in head-injured patients. Am J Gastroenterol 1998; 93:1108-1112.

9. Saxe JM, Ledgerwood AM, Lucas CE, LucasWF. Lower esophageal sphincter dysfunction precludes safe gastric feeding after head injury. J Trauma 1994; 37:581-584.

10.  Pedoto MJ, O'Dell MW, Thrun M, Hollifield D. Superior mesenteric artery syndrome in traumatic brain injury: two cases. Arch Phys Med Rehabil 1995; 76:871-875.

11.  Moore FA, Moore EE, Sauaia A. Postinjury multiple organ failure in trauma. editors. In: Mattox KL, Feliciano DV, Moore EE. New York: McGraw-Hill; 1999.p.1427-1459.

12.  Harbrecht BG, Zenati MS, Doyle HR, McMichael J, Townsend RN, Clancy KD, et al. Hepatic dysfunction increases length of stay and risk of death after injury. J Trauma 2002; 53:517-523.

13.  Bone RC. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med 1996; 125:680-687.

14.  Clark JA, Coopersmith CM. Intestinal crosstalk: a new paradigm for understanding the gut as the "motor" of critical illness. Shock 2007; 28:384-393.

15.  Rotstein  OD.  Modeling  the  two-hit  hypothesis  for  evaluating  strategies  to  prevent  organ  injury  after shock/resuscitation. J Trauma 2003; 54:S203-206.

16.  Giroud M, Milan C, Beuriat P, Gras P, Essayagh E, Arveux P, et al. Incidence and survival rates during a two- year period of intracerebral and subarachnoid hemorrhages, cortical infarcts, lacunes and transient ischemic attacks. The stroke registry of Dijon: 1985-1989. Int J Epidemiol 1991; 20:892-899.

17.  Shahrokhi N, Khaksari M, Soltani Z, Mahmoodi M, Nakhaee N. Effect of sex steroid hormones on brain edema, intracranial pressure, and neurologic outcomes after traumatic brain injury. Can J Physiol Pharmacol 2010; 88:414-421.

18.  Soltani Z, Khaksari M, Shahrokhi N, Nakhaei N, Shaibani V. Effect of combined administration of estrogen and progesterone on brain edema and neurological outcome after traumatic brain injury in female rats. Iran J Endocrinol Metabol 2010; 10:629- 638.

19.  Bradesi S, Eutamene H, Fioramonti J, Bueno L. Acute restraint stress activates functional NK1 receptor in the colon of female rats: involvement of steroids. Gut 2002; 50:349-354.

20. Mathias JR, Clench MH. Relationship of reproductive hormones and neuromuscular disease of the gastrointestinal tract. Dig Dis 1998; 16:3-13.

21.  Olson ME, Bruce J. Ovariectomy, ovariohysterectomy and orchidectomy in rodents and rabbits. Can Vet J 1986; 27:523–527.

22. Gang C, Jinxin S, Yasuo D, Hongxia Y, Chunhua H. Progestrone prevents traumatic brain injury-induced intestinal nuclear factor kappa B activation and proinflammatory cytokines expression in male rats. Mediators Inflamm. 2007; 2007:93431.

23.   Marmaro A, Montasser A. A new model of diffuse brain injury in rats. Neurosurg 1994; 80:291-300.

24. Nabavizadeh F, Shahrani M, Vahedian Z, Vahedian M. Marjoram increases basal gastric acid and pepsin secretions in rat. Phytother Res 2007; 21:1036–1038.

25.  Anson ML. The estimation of pepsin, tyrosin, papain, and cathepsin with hemoglobin. J Gen Physiol 1938: 20;22:79-89.

26. Kawakubo K, Fujishima M. Management of gastrointestinal mucosal damage in patients with cerebrovascular disease. Nippon Rinsho 2002; 60:1573-1579.

27. Smith A, Contreras C, Hyun Ko K, Chow J, Dong X, Tuo B, et al. Gender-specific protection of estrogen against   gastric   acid-induced   duodenal   injury:   stimulation   of   duodenal   mucosal   bicarbonate   secretion. Endocrinology 2008; 149:4554-66

28. Drago F, Montoneri C, Varga C, Làszlò F. Dual effect of female sex steroids on drug-induced gastroduodenal ulcers in the rat. Life Sci 1999; 64:2341-2350.

29. Kitagawa H, Fujiwara M, Osumi Y. Effects of water-immersion stress on gastric secretion and mucosal blood flow in rats. Gastroenterology 1979; 77:298-302

30. Aguwa CN. Effects of exogenous administration of female sex hormones on gastric secretion and ulcer formation in the rat. Eur J Pharmacol 1984; 104:79–84.

31. Amure BO, Dmole AA. Sex hormones and acid gastric secretion induced with carbachol, histamine and gastrin. Gut 1970; 11:641–645.

32. Girma K, Janczewska I, Romell B, Seensalu R, Sandin A, Wilander E, et al. Twenty-four-hour basal and repetitive pentagastrin-stimulated  gastric  acid  secretion  in  normal  and  sham-operated  rats  and  in  rats  after gonadectomy or treatment with estradiol or testosterone. Scand J Gastroenterol 1997; 32:669-675.

33. Esplugues JV, Barrachina MD, Beltrán B, Calatayud S, Whittle BJR, Moncada S. Inhibition of gastric acid secretion by stress: A protective reflex mediated by cerebral nitric oxide. Proc Natl Acad Sci USA 1996; 93:14839–14844.

34. Shimozawa N, Okajima K, Harada N. Estrogen and isoflavone attenuate stress-induced gastric mucosal injury by inhibiting decreases in gastric tissue levels of CGRP in ovariectomized rats. Am J Physiol Gastrointest Liver Physiol 2007; 292:G615-G619.

35. Hogan AM, Collins D, Baird AW, Winter DC. Estrogen and its role in gastrointestinal health and disease. Int J Colorectal Dis 2009; 24:1367-1375.

36. Anders S, Cheyanne C, Kwang H, Jimmy C, Xiao D, Biguang T, et al. Gender-specific protection of estrogen against gastric acid-induced duodenal injury: stimulation of duodenal mucosal bicarbonate secretion. Endocrinology 2008; 149:4554–4566.

37. Günal Ö, Oktar B K., Özçnar E, Sungur M, Arbak  S, Yeen BÇ. Estradiol treatment ameliorates acetic acid- induced gastric and polonic injuries in rats. Inflammation  2003; 27:351-359.

38. Sayegh  M , Elder J B. Effect of gonadectomy on epidermal growth factor values in the gastrointestinal tract of male and female CD-1 mice. Gut 1995; 36:558–563.

39. Zhou Ml, Zhu L, Wang J, Hang CH, Shi JX. The inflammation in the Gut after experimental subarachnoid hemorrhage.  J Surg Res 2007; 137:103-108.

40. Shan J, Resnick  LM, Liu QY, Wu X C, Barbagallo  M, Pang P K. Vascular effects of 17 beta-estradiol in male Sprague-Dawley rats. Am J Physiol Heart Circ Physiol 1994; 266:H967-H973.

41. Campbell-Thompson M, Reyher   KK, Wilkinson   LB. Immunolocalization of estrogen receptor α and β in gastric epithelium and enteric neurons. J Endocrinol 2001; 171:65–73.

42. Bubenik GA, Blask DE, Brown GM, Maestroni GJ, et al. Prospects of the Clinical Utilization of Melatonin. Biol Signals Recept 1998; 7:195-219.

43. Lindh A, Carlström K, Eklund J, Wilking N. Serum steroids and prolactin during and after major surgical trauma. Acta Anaesthesiol Scand 1992; 36:119-124.

44. Isomoto H, Inoue K, Kohno S. Interleukin 8 levels in esophageal mucosa and long- term clinical outcome of patients with reflux esophagitis. Scand J Gastroentrol 2007; 42:410-411.

45. Wang Y, Hu F, Wang ZJ, Wang GX, Zhang ZH, Xie P, et al.  Administration of bone marrow- derived stem cells suppresses cellular necrosis and apoptosis induced by reperfusion of ischemic kidneys in rats. Chin Med J 2008; 121:268-271.

46. Du D, Maa X, Zhanga J, Zhanga Y, Zhoua X, Lia Yu. Cellular and molecular mechanisms of 17β-estradiol postconditioning protection against gastric mucosal injury induced by ischemia/reperfusion in rats.   Life Sci 2010; 86:30-38.

47. Ohja KN, Wood DR. The inhibitory effect of stilboestrol on gastric secretion in cats. Br J Pharmac 1950; 5:389- 394.

48. Oluwole FS, Bolarinwa AF. Effects of gonadectomy on indomethacin- induced ulceration and peptic activity in rats. Afr J Med Med Sci 1990; 19:139-143.

49. Wichmannb MW, Zellwegera R, DeMasoa CM., Ayalac A, Chaudry IH. Enhanced immune responses in females, as opposed to decreased responses in males following heamorragic shock and resuscitation. Cytokine 1996; 8:853-863

50.  Kotani  T,  Murashima  Y,  Kobata  A,  Amagase  K,  Takeuchi  K.  Pathogenic  importance  of  pepsin  in ischemia/reperfusion-induced gastric injury. Life Sci 2007; 80:1984-1992.

51. Gritti I, Banfi G, Roi GS. Pepsinogens: physiology, Pharmacology, pathophysiology and exercise. Pharmacol Res 2000; 41:265-281.

52. Lehmann FS, Stalder A. Hypotheses on the role of cytokines in peptic ulcer disease. Eur J Clin Invest 1998; 28:511- 519.

53. Hunt JN, Murray FA.Gastric function in pregnancy. J Obstet Gynaecol Br Emp 1958; 65:78- 83.

54. Piyachaturawat P, Sretarugsa P, Limlomwongse L, Sahaphong S. Effect of estradiol treatment on the secretion and structure of gastric H+ and pepsin-secreting cells in the rat. Res Commun Chem Pathol Pharmacol 1983; 42:81-93.

55. Pfaffl MW, Lange IG, Meyer HH. The gastrointestinal tract as target of steroid hormone action: quantification of steroid. J Steroid Biochem Mol Biol 2003; 84:159-166.

56. Blandizzi C, Lazzeri G, Colucci R, Carignani D, Tognetti M, Baschiera F, et al. CCK1 and CCK2 receptors regulate gastric pepsinogen secretion. Eur J Pharmacol 1999; 373:71-84.

57. Yang X, Liu R, Dong Y. Regulative effects of ovarian steroids on rat gastric motility and sensitivity. Sheng Li Xue Bao 2006; 58:275-280.

58.  Okumura  T,  Uehara  A,  Okamura  K,  Takasugi  Y,  Namiki  M.  Inhibition  of  gastric  pepsin  secretion  by peripherally or centrally injected interleukin-1 in rats. Biochem Biophys Res Commun 1990; 167:956-961.

59. Black H E. The Effects of Steroids upon the Gastrointestinal Tract. Toxicol Pathol 1988; 16:213-222.

60. Samuels T L, Johnston N. Pepsin as a causal agent of inflammation during nonacidic reflux. Otolaryngol Head Neck Surg 2009; 141:559-563.

61. Modlin IM, Basson MD, Adrian TE, Sussman J. Pepsinogen release and acid secretion from human and guinea pig gastric mucosa compromised by hypoxia, endotoxin, or critical illness. Scand J Gastroenterol 1990; 25:865- 875.

62. Baron J H. Sex, gonads, sex hormones and histamine-stimulated gastric acid and serum pepsinogen.  Inflamm Res 1997; 46:260-264.