Sex and Gender Differences in Gastroesophageal Reflux Disease

Abstract

It is important to understand sex and gender-related differences in gastroesophageal reflux disease (GERD) because gender-related biologic factors might lead to better prevention and therapy. Non-erosive reflux disease (NERD) affects more women than men. GERD symptoms are more frequent in patients with NERD than in those with reflux esophagitis. However, men suffer pathologic diseases such as reflux esophagitis, Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC) more frequently than women. The prevalence of reflux esophagitis is significantly increased with age in women, especially after their 50s. The mean age of EAC incidence in women is higher than in men, suggesting a role of estrogen in delaying the onset of BE and EAC. In a chronic rat reflux esophagitis model, nitric oxide was found to be an aggravating factor of esophageal injury in a male-predominant way. In addition, the expression of esophageal occludin, a tight junction protein that plays an important role in the esophageal defense mechanism, was up-regulated in women. This explains the male predominance of reflux esophagitis and delayed incidence of BE or EAC in women. Moreover, the symptoms such as heartburn, regurgitation, and extra-esophageal symptoms have been more frequently reported by women than by men, suggesting that sex and gender play a role in symptom perception. Differential sensitivity with augmented symptoms in women might have diagnostic and therapeutic influence. Furthermore, recent studies have suggested that hormone replacement therapy has a protective effect against esophageal cancer. However, an anti-inflammatory role of estrogen remains compelling, which means further study is necessary in this area.

Keywords: Adenocarcinoma; Barrett esophagus; Esophagitis; Estrogen; Gender.

Figure 1

Flow chart documenting the results of search strategy.

Figure 2

Schematic presentation of epidemiological trends in gastroesophageal reflux disease (GERD)-related disorders. While typical GERD symptoms are balanced between comparator groups, the distribution of complications becomes progressively skewed in gender, geographic and racial distribution. *GERD symptoms are similar between Western and Middle Eastern countries, but are lower in Eastern countries (adapted from Boeckxstaens et al16).

Figure 3

Schematic of the proposed effects of aging and hormonal changes. Proposed mechanism of the loss of mucosal epithelial integrity and microbial translocation and the effects of hormonal changes associated with aging. Reduced levels of E2 due to aging, especially, after women’s menopause, can potentially increase epithelial permeability and microbial translocation (adapted from Grishina et al60).