|Year : 2015 | Volume
| Issue : 1 | Page : 75-80
The effects of female sexual steroids on gastric function and barrier resistance of gastrointestinal tract following traumatic brain injury
Zakieh Keshavarzi1, Mohammad Khaksari2
1 Departments Physiology, Bojnurd University of Medical Sciences, Bojnurd, Iran
2 Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran
|Date of Submission||29-Dec-2013|
|Date of Decision||29-Jul-2014|
|Date of Acceptance||02-Sep-2014|
|Date of Web Publication||21-Jan-2015|
Departments Physiology, Bojnurd University of Medical Sciences, Bojnurd
Source of Support: The study funding was provided by Physiology
Research Center, Kerman University of Medical Sciences, Kerman, Iran, Conflict of Interest: None
| Abstract|| |
Aim: The aim was to assess the alteration of gastric function and barrier function of gastrointestinal (GI) tract following diffuse brain injury in varying ovarian hormone status. Materials and Methods: Diffuse traumatic brain injury (TBI) was induced by Marmarou method. Rats were randomly assigned into 10 groups: Intact, sham + ovariectomized female (OVX), TBI, TBI + OVX, vehicle, estradiol (E2), progesterone (P), E2 + P, estrogen receptor alpha agonist and estrogen receptor beta agonist (DPN). Endotoxin levels were measured using enzyme-linked immunosorbent assay method. All the parameters were measured 5 days after TBI. Results: Intragastric pressure was significantly decreased in TBI as compared to the intact group (P < 0.001) and this was lower in TBI group versus TBI + OVX group (P < 0.05). Pretreatment with steroid hormones and their agonists did not have any effect on the gastric pressure compared to TBI + OVX or vehicle groups. Inflammation, congestion, ulcer and erosion were seen in the TBI rats. All treatment groups worsen the tissue condition so that the presence of thrombosis also was seen. The trauma induction did not have any effect on the serum and intestinal endotoxin levels. DPN had caused a significant reduction in serum levels of endotoxin compared with OVX + TBI group (P < 0.05). Conclusion: Pretreatment with sexual steroids is not useful in the treatment of GI dysfunction induced by TBI. The treatment with all sexual female hormones worsens the gastric tissue condition. Furthermore, the applied weight was not enough for releasing of endotoxin. It seems that estrogen reduced the endotoxin levels by estrogen beta receptor.
Keywords: Brain injury, estrogen receptor beta agonist, estrogen, estrogen receptor alpha agonist, progesterone
|How to cite this article:|
Keshavarzi Z, Khaksari M. The effects of female sexual steroids on gastric function and barrier resistance of gastrointestinal tract following traumatic brain injury. J Pharm Bioall Sci 2015;7:75-80
|How to cite this URL:|
Keshavarzi Z, Khaksari M. The effects of female sexual steroids on gastric function and barrier resistance of gastrointestinal tract following traumatic brain injury. J Pharm Bioall Sci [serial online] 2015 [cited 2019 Oct 20];7:75-80. Available from: http://www.jpbsonline.org/text.asp?2015/7/1/75/149815
Brain-gut axis can play an important role in the development of gastrointestinal (GI) dysfunction following traumatic brain injury (TBI). , GI dysfunction happens commonly in patients with TBI.  Dysfunction of the different parts of GI tract led to corresponding symptoms such as GI bleeding, , gastric reflux  and decreased intestinal peristalsis,  essentially due to mucosal damage and alteration of GI motility. 
Many patients with head injuries do not endure the enteral feedings. This intolerance is showed by vomiting, abdominal distention, delayed gastric emptying, esophageal reflux and decreased intestinal peristalsis, suggesting that GI dysfunction is a common phenomenon following TBI. Moreover, TBI can induce main damages of gastric structure and impairment of gut barrier function, which marked with mucosal atrophy. 
It is generally recognized that the intestine may function as an important organ in the progression of severe complications under critically ill situations, including trauma, burns and shock.  Major trauma can induce some intestinal events such as intestinal cytokine response,  increased intestinal permeability,  translocation of intestinal bacteria and endotoxin,  leading to systemic inflammatory response syndrome and sepsis with subsequent multiple organ failure.  Bacterial endotoxin (lipopolysaccharide) may worsen the inflammatory response of injured brain, leading to the invasion of granulocytes into the brain and failure of the blood-brain barrier. 
In addition, it is now clear that biological sex alters the incidence of, and outcome from, ischemic and TBI. For example, male sex is an approved risk factor for stroke, and in most epidemiological series, stroke occurs more commonly in men versus women. 
Uses of estrogen or progesterone (P) alone or a combination of these two hormones reduce brain edema following TBI. This determines the anti-inflammatory role of female sexual steroids.  It has been reported that steroid hormones, especially P and estrogen, have effects on the gastric motility and secretions. 
Because enteral nutrition and enterogenous sepsis are two of the important factors affecting the outcomes of comatose patients with TBI, the maintenance of normal GI integrity is believed to be helpful in improving the outcomes of head injured patients.  And, with regard to function of female sexual hormones in reducing of injury after trauma in our previous results of our research group, , the purpose of this experiment was to assess the alteration of gastric function and barrier function of GI tract following diffuse brain injury in ovariectomized rats of varying ovarian hormone status (estrogen, P, or estrogen receptor agonists treated).
| Materials and Methods|| |
Female Wistar rats (200-250 g) were purchased from Animal Center of Kerman University of Medical Sciences, Kerman, Iran. The rats were housed in temperature and humidity controlled animal quarters with a 12-h light/dark cycle. All procedures were approved by the Institutional Animal Care Committee and were in accordance with the guidelines of the National Institutes of Health on the care and use of animals.
Following anesthesia, the animals were placed in left lateral position. The left flank of the rats (landmark the ovaries: Caudal end of the ribs on left lateral side of the animal) was shaved with electric clippers and furs removed completely. The area was washed using chlorhexidine scrub and ethanol 70% respectively. A 2 cm incision was made on the middle part of the abdomen using a scalpel blade. Incision was of minimum length to allow the extrusion of ovaries. The skin of rats is so loose that the skin incision can be retracted from one side to the other to remove each ovary from the same skin incision. Then, 1.5-2 cm peritoneal incision was made with iris scissors or a scalpel blade. The left ovary and associated fat were easily located and exteriorized by gentle retraction. The procedure was repeated for right ovary through same incision. After ovaries' removal, peritoneal cavity and skin were closed with absorbable sutures. 
Two weeks after the operation, the rats were randomly divided into 10 groups (n = 7 in each group): (1) Intact group: The animals that were neither ovarectomized nor given any drugs; (2) sham group: Ovariectomized female (OVX) rats were sham surgically, but without actual induction of TBI; (3) TBI group: Intact rats were injured using the TBI device; (4) OVX + TBI group: OVX rats were injured using the TBI device; (5) vehicle group: OVX rats were injected with 0.1 ml of DMSO; (6) estrogen (E2) group (Aboreyhan, Iran): OVX rats were injected with 17 β-estradiol (E2) (1 mg/kg);  (7) P group (Aboreyhan, Iran): OVX rats were injected with P (16 mg/kg);  (8) estrogen + P (E2 + P) group: OVX rats were injected with a combination of both 17 β-E2 (1 mg/kg) and P (16 mg/kg); (9) estrogen receptor alpha agonist (PPT) group: OVX rats were injected with PPT (1 mg/kg);  (10) estrogen receptor beta agonist (DPN) group: OVX rats were injected with DPN (1 mg/kg).  Rats in the treatment groups received injections at 1 and 6 h and 1, 2, 3, 4, and 5 days after the surgery (subcutaneously for the first and intraperitoneally for the remaining six). 
Traumatic brain injury induction
The rat model of diffuse head injury was engaged as described with Marmarou method.  After a midline incision in the scalp, a metallic disc was fixed to the skull surface with dental cement. The animal was located in a prone position on a foam bed, and a 300-g weight was dropped through a Plexiglas tube from a 2-m height. The rat body temperature was controlled until recovery from anesthesia by a thermostatic heating pad coupled to a rectal thermal probe. Brain injury-induced apnea was then treated for 3 min with 100% oxygen administration and chest compression to stimulate the respiration. This model is commonly associated with 20% of mortality within the first 5 min postinjury, and no delayed mortality was observed thereafter. After operation procedures, the rats were returned to their cages. The animals were kept in cages for 5 days and then were anesthetized 5 days after injury for the motility measurement.
In the 5 th day after induction of TBI, animals were anesthetized with sodium thiopental (50 mg/kg, intraperitoneally [i.p.]). Depth of anesthesia was controlled throughout the experiment by the pedal withdrawal (toe pinch) reflex every 30-45 min. If the pedal withdrawal reflex was observed, a supplemental dose of urethane (0.4 g/kg, i.p.) was administered to retain adequate anesthesia. Clean, but not sterilized, instruments were used to do the surgical procedures. The trachea was surgically exposed and cannulated by a polyethylene catheter (2 mm, O.D.) to facilitate spontaneous respiration. After a midline laparotomy, both the stomach and the duodenum were exposed. At the beginning of each experiment, the lumen of the stomach was gently rinsed with isotonic saline (pH 7, 37°C) until gastric washout was clear. The tubing was connected to a pressure transducer, which was joined to a bridge amplifier (MacLab). Data were saved for analysis at a later time. The stomach was inflated by introducing warm saline (2-3 ml) into the balloon, to get a baseline pressure of 6-15 mmHg. After waiting for 30 min to reach a steady state, gastric motility was measured. 
Endotoxin assay by enzyme-linked immunosorbent assay
Rats were given an overdose of sodium pentobarbital (75 mg/kg, i.p.), then the intestinal tissue was quickly removed and immediately frozen in 2-methylbutane (35jC) on dry ice. Each section of intestinal tissue was weighed and homogenized in T-PERk Tissue Protein Extraction Reagent (Pierce, Rockford, IL, US) with 0.01% Triton-100 and protease inhibitor cocktail (Pierce) (300 mg tissue per 3 ml of the reagent). Following homogenization, samples were centrifuged 10,000 g for 15 min, and the supernatant was collected as homogenate. Enzyme-linked immunosorbent assay kit for endotoxin measurement was purchased from Uscn life company (China), and the manufacturer's protocols were followed.
The 10% buffered formalin-fixed stomach was embedded in paraffin, sectioned at 4 mm thickness with a microtome and stained with hematoxylin and eosin. The sections were examined under light microscope. In regarding to Sydney system, inflammation, congestion, hemorrhage, erosion and ulcer in gastric tissue were determined. 
Software SPSS 11.5 was used in the statistical analysis. Each parameter was expressed as mean ± standard error of the mean, and compared using one-way analysis of variance, followed by least significant difference test. The level of significance was P < 0.05.
| Results|| |
Intragastric pressure changes in ovariectomized female and intact animals after induction of brain trauma
The effect of TBI on the intragastric pressure in different groups is shown in [Figure 1]. Intragastric pressure was decreased in TBI group (6.5 ± 0.35 mmHg) when compared to intact group (10.27 ± 0.42 mmHg) (P < 0.001). On the other hand, intragastric pressure was lower in TBI group versus TBI + OVX group (P < 0.05).
|Figure 1: Intragastric pressure (mmHg) in different groups (n = 7 in each group) after TBI. Data are presented as mean ± SEM. (a) P < 0.001, TBI + OVX versus intact group, (b) P < 0.05, TBI + OVX versus TBI group. TBI: Traumatic brain injury, OVX: Ovariectomized female rats, sham + OVX: Female animals without ovaries, OVX + TBI: Traumatic animals without ovaries, SEM: Standard error of the mean|
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Effect of female sex steroids on the intragastric pressure in traumatic brain injury + ovariectomized female animals
Changes of intragastric pressure in different groups are shown in [Figure 2]. There is not any difference in intragastric pressure between different treated groups with vehicle or TBI + OVX group. Intragastric pressure in 17 β-E2 treated animals significantly was lower (7.11 ± 0.53 mmHg) compared to P (8.89 ± 0.27 mmHg) (P < 0.05) or estrogen + P combination group (9.08 ± 0.51 mmHg) (P < 0.01).
|Figure 2: Intragastric pressure (mmHg) in different groups (n = 7 in each group) after traumatic brain injury. Data are presented as mean ± SEM. (a) P < 0.01, P and E2 + P groups versus E2 group. Abbreviations: E2: Estradiol, P: Progesterone, SEM: Standard error of the mean|
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Effect of alpha and beta estrogen receptor agonists on intragastric pressure in traumatic brain injury + ovariectomized female animals
As shown in [Figure 3], intragastric pressure in TBI + OVX and vehicle group was (8.15 ± 0.45 mmHg) and (7.76 ± 0.55 mmHg), respectively, that there is no difference after treatment with PPT and DPN agonists.
|Figure 3: Intragastric pressure (mmHg) in different groups (n = 7 in each group) after traumatic brain injury. Data are presented as mean ± SEM. There was no significant difference between different groups. PPT: Estrogen receptor alpha agonist, DPN: Estrogen receptor beta agonist, SEM: Standard error of the mean|
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Serum and intestinal levels of endotoxin in intact and ovariectomized female rats following traumatic brain injury and treatment with different steroids
Trauma induction didn't have any effect on the serum endotoxin levels in intact and OVX animals. Vehicle increased the serum levels of endotoxin compared to OVX + TBI (P < 0.001), however there is no significant difference between other treatment groups. DPN had caused a significant reduction in serum levels of endotoxin compared to OVX + TBI group (P < 0.05). Intestinal levels of endotoxin increased in TBI animals when compared to OVX + TBI or vehicle groups. The treatment with all of the female sexual hormones did not have any effect on the intestinal levels [Table 1].
Histopathological examination showed that the morphology of gastric tissue was approximately normal in the control rats (a). In the rats subjected to TBI the following changes could be observed: Inflammation, congestion, ulcer and erosion (b). The severity of histopathological changes was decreased in OVX + TBI group, so that the ulcers were disappearing, but inflammation and congestion were dominant (c). Treatment with E2, P, combination of these steroids, PPT and DPN worsen the tissue condition so that the presence of thrombosis also was seen. In addition, the number of ulcers was increased and more severe inflammatory cells infiltrate emerges in the gastric tissue (d) [Figure 4].
|Figure 4: Photomicrographs showing histopathological changes in the different groups. (a) The normal gastric morphology of the control animals (H and E; original magnification, ×10). (b) The histopathoglogical changes in the gastric tissue of the rats in the TBI group. These changes include inflammation, congestion, ulcer and erosion (H and E; original magnification, ×4). (c) The histopathology changes in OVX + TBI group including inflammation and hemorrhage (H and E; original magnification, ×20). (d) The histology changes in treatment groups including inflammation, hemorrhage, ulcer, thrombosis (H and E; original magnification, ×4). TBI: Traumatic brain injury, OVX: Ovariectomized female|
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| Discussion|| |
In the present study, it was found that intragastric pressure significantly reduced following brain trauma. In the agreement with our studies, it was shown that vomiting, abdominal distension and increased gastric remnants after neurological trauma suggesting the presence of abnormal gastric movements.  It has been observed that gastric movements were inhibited during the 1 st min by bilateral carotid artery ligation and cerebral ischemia.  Further research has identified the role of Cajal interstitial cells (ICC) in motility disorders following ischemia.  Exact pathogenesis of gastric motility disorders following TBI is not clear. However disorders in vagus neurons, enteric neurons, ICC, smooth muscle cells, or hormonal factors have been expressed. Also, disorganized gastric myoelectric activities may be another possible cause. ,
Melro et al. reported that gastric emptying did not change following mild to moderate ischemic brain injury, which is inconsistent with our results.  Possible reasons for this controversy could be explained by ischemic brain injury type, time and measurement method of gastric motility.
In another part of our study, it was shown that consumption of sexual steroids and their agonists did not have any effect on the gastric pressure. There are a lot of studies with controversial results that we pointed to some of them. Milenov shown that electrical spike potentials recorded from the gastric antrum and jejunum of ovarectomized dogs decreased after P treatment.  It was reported that estrogen administration inhibits gastric emptying and intestinal transit while P increased GI movements.  Wang et al. reported that P inhibited the contractile activity of isolated gastric strips in rats.  It has been shown that pregnancy is associated by changes in GI motor activity such as reduced gallbladder contraction, decreased gastric emptying and intestinal transit and colon.  Liu et al. demonstrated that the propagation rate of basic electrical rhythm decreased from the antrum region of OVX rats treated with P. Also, they reported that low dose of P increased the GI movement while its high dose reduced the movement that this explained why different effects of P have been seen on the gastric emptying and intestinal transit.  Another report showed that the E2 and E2 + P inhibited gastric movement while P increased gastric emptying.  Overall, the majority of researchers believe that the estrogen delayed gastric emptying in animal models.
Different mechanisms of the inhibitory function of estrogen has been proposed including: Induction of nitric oxide release from GI noncholinergic nonadrenergic nerves,  stimulation of cholecystokinin by cholecystokinin receptor type A  and changes in vagus nerve activity.  Also, gastric motility can be changed by sex steroids and this response mediated by changing the hypothalamus-pituitary-adrenal axis. 
Present results showed that intestinal and serum endotoxin levels did not change following TBI that is consistent with the Feighery et al. study who reported that serum endotoxin levels did not differ compare to control following trauma induction. 
The study results are inconsistent with some other results. Hong et al. demonstrated that endotoxin plasma levels have two peaks after trauma that the first peak may be associated with GI mucosal damage induced by acute splenic ischemia due to stimulated sympathic nerve. The second peak may be caused by severe mucosal damage such as ulcers and focal necrosis of the epithelial.  Cheng et al. also reported that blood endotoxin levels significantly increased after induction of hemorrhage shock that it will reach to peak values at 3-6 h after induction of shock.  Furthermore, it was reported that GI ischemia-reperfusion injury due to hemorrhage shock lead to atrophy and increased permeability of the intestinal mucosa to endotoxin.  Some reasons for this controversy with other results could be due to differences in measurement methods, measurement time and model of brain traumatic injury induction.
In another part of our study indicated that despite the lack of estrogen effect on endotoxin levels, but DPN caused a significant reduction in serum endotoxin levels. Braniste et al. also reported that E2 strengthen the epithelial barrier and decreased the colonic permeability through DPN. 
The present histopathology results showed that inflammation, hemorrhage, congestion, erosion and ulcer were seen in TBI group. However, there was no evidence of ulcer following trauma in OVX rats, but inflammation and hemorrhage were seen as before that this indicates that female sexual hormones are involved in gastric tissue histopathological changes. In the confirmation with our results, the treatment with sexual steroids was associated with inflammation, hemorrhage, congestion and erosion. However, the remarkable point about steroids was the appearance of big ulcers along with intravascular thrombosis. These results confirm that treatment with sexual steroids may cause to worsening of the condition, and we should be caution about the using of female sexual steroids. The present results were coordinated with other results about the formation of vascular thrombosis using of contraceptive pills. Several studies showed that the use of oral contraceptive pills containing high estrogen and P levels lead to enhancement of intravascular thrombosis risk.  However, contradictory results have also been seen, for example, it has been reported that ovariectomy in rats increased the thrombosis risk and treatment with E2 and raloxifene reduced the intravascular thrombosis and this anti-thrombosis effect associated with increased cyclooxygenase 2 expression and inhibition of platelet binding. 
Dimant reported increased sympathetic nervous system activity following stroke induced a massive release of catecholamines resulting in vasoconstriction, which reduced splenic perfusion and led to the ulceration. Delayed gastric emptying following the disruption of central nervous system and GI tract link may be involved in the formation of peptic ulcers. 
Some other studies showed that P treatment reduced the GI disorders after trauma that is inconsistent with our results. , Possible reasons for this controversy with other studies can may be resulted from the kind of head injury, duration of drug using, the method of measuring of injury severity and type of vehicle that it may be the effect on drug metabolism.
It was concluded that pretreatment with sexual steroids is not useful in the treatment of GI dysfunction induced by TBI. The treatment with all sexual female hormones worsens the gastric tissue condition. Also, the applied weight was not enough for releasing of endotoxin. It seems that the estrogen reduced the endotoxin levels by estrogen beta receptor. However, we need to have more research about the applied weight and dose of female sexual hormones.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]