Why is reflux esophagitis a predominantly male disease?
J. Sarosiek, R.W. McCallum (Kansas City)
The answer to this question requires an insight into two major dimensions of the pathogenesis of reflux esophagitis (RE) as they relate to gender. The first dimension is an acid exposure time as an index of incompetence of LES and impairment of esophageal motility. The second is the status of esophageal pre-epithelial barrier, the major protective mechanism combating abnormal gastroesophageal reflux (GER) and its major aggressive component-acid.
Although generally both males and females have always been enrolled in the study protocols related to 24-hour pH monitoring in clinical diagnostic centers, the issue of the potential difference in acid exposure time between males and females has been generally overlooked [1-3]. This is surprising considering the fact that gastric acid secretion results are analyzed separately for males and females and there is a gender-related difference in these values.
Recently a new tool for the diagnosis of an esophageal mucosal exposure to duodenogastroesophageal refluxate assessing contamination with duodenal secretion called Bilitec, has been introduced into clinical diagnostic armamentarium [4, 5]. This new bile monitoring device required both clinical validation and an establishment of control values for asymptomatic, presumably healthy, population of volunteers . Unfortunately, presumably due to small control sample size, the potential difference between males and females has not been addressed [4, 5].
In groups of patients with GERD, RE and Barrett's esophagus which are gradually dominated by males, the issue of gender in reported abnormalities has also not been disclosed [4). Even in an elegant review of prolonged ambulatory pH monitoring by Mattox and Richter the issue of a gender has only been briefly mentioned . As far as acid exposure time is concerned, as measured by 24-hour pH monitoring, there is only a handful of papers addressing the difference between males and females within control groups and population of patients with RE . In this paper the gender issue has been analyzed and significantly higher number of reflux episodes > 5 minutes (p = 0.008) and nearly significant difference for percentage of total acid exposure time (p = 0.03), the total number of reflux episodes (p = 0.02) and the longest acid reflux episode (p = 0.02) were demonstrated . These data indicate the gender difference could play some role promoting predominance of males among RE population; however, the issue still requires further investigation on larger populations of controls and patients with RE.
Assuming that control males have a trend only to a greater exposure of the esophageal mucosa to gastroesophageal refluxate but still dominate population of patients with RE, this may imply that males have more sensitive esophageal mucosa to GER and, therefore, seek more help or that males more frequently develop endoscopic RE since they have impaired protective mechanisms.
If the esophageal mucosa in males is more sensitive to acid and more easily leads to development of symptoms, this should prevent the development of RE, and, therefore, females should dominate RE population. In addition, in relevant papers dealing with the issue of the role of physiological, environmental and psychological factors in pain, perception gender difference has never been demonstrated [7-9]. One may surmise, therefore, that the difference in protective mechanisms between males and females may shed some light on this gender related preponderance of males to the development of endoscopic RE.
Protective mechanisms in humans operate at three overlapping levels: 1) pre-epithelial defense, 2) epithelial defense, and 3) post-epithelial defense [10, 11]. In humans, however, only components of the pre-epithelial barrier can be clinically measured [11-26].
If control males have a trend to greater exposure of the esophageal mucosa to acid and significantly greater number of reflux episodes lasting longer than 5 min , they should have stronger protective mechanisms in order to balance this exposure. In our preliminary study we did not find statistical difference in the rate of salivary secretion (ml/min) between control males and females both during basal conditions, mastication (chewing the soft parafilm) and stimulation intraesophageal mechanical (catheter and balloons) and chemical (HCl and HCl/pepsin) stimulation mimicking the nature GER scenario (unpublished results). We have not been able to find a significant difference in the rate of salivary EGF and PGE2 output in male and female controls (unpublished results). Considering the fact that control males have significantly higher number of GER episodes lasting more than 5 min  and do not have enhanced salivary secretory response to intraesophageal acid and pepsin solution, this may at least partly explain why predominantly males develop endoscopic RE.
The protective secretory response within the esophageal mucosa to exposure to HCl/pepsin in control and RE males and females is currently under investigation. In general, the entire population of patients with RE exhibits significantly lower rate of salivary and esophageal EGF secretion and the lower rate of esophageal glycoconjugates (predominantly mucin) output than controls [14, 18, 26]. The lower rate of esophageal EGF secretion persists after healing of endoscopic erosive changes [27, 28]. If diminished protective potential of salivary and esophageal secretions affects, predominantly males, this could explain more severe damage to the esophageal mucosa by GER. If males with RE have in general greater acid exposure time than females (in a similar fashion as it has been demonstrated in control males) and if their protective factors within salivary and esophageal secretion are similar to females, this excessive reflux would be the leading factor in the development of more severe mucosal pathology.
We believe that the role of gender-related factors in the pathophysiology of GERD, RE and complications requires further study and may reveal clinically relevant information helping to tailor the best treatment regimen for this most prevalent disease.
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26. Rourk RM, Namiot Z, Sarosiek J, Yu Z, McCallum RW. Impairment of salivary epidermal growth factor secretory response to esophageal mechanical and chemical stimulation in patients with reflux esophagitis. Am J Gastroenterol 1994;89:237-244.
27. Edmunds MC, Namiot Z, Sarosiek J, Rourk RM, Yu Z, McCallum RW. Esophageal epidermal growth factor impairment persists despite healing of endoscopic changes in patients with reflux esophagitis. Gastroenterology 1994;106:A73.
28. Edmunds MC, Marcinkiewicz M, Namiot Z, McCallum RW, Sarosiek J. Impaired esophageal epidermal growth factor secretion prevails despite healing of endoscopic reflux esophagitis: its pathogenetic implications. Dig Dis Sci 1997 (Submitted).