Gender difference in gastro-esophageal reflux diseases

Abstract

The incidence of esophageal adenocarcinoma (EAC) has risen sharply in western countries over the past 4 decades. This type of cancer is considered to follow a transitional process that goes from gastro-esophageal reflux disease (GERD) to Barrett’s esophagus (BE, a metaplastic condition of the distal esophagus), a precursor lesion and ultimately adenocarcinoma. This spectrum of GERD is strongly predominant in males due to an unidentified mechanism. Several epidemiologic studies have described that the prevalence of GERD, BE and EAC in women is closely related to reproductive status, which suggests a possible association with the estrogen level. Recently, we revealed in an in vivo study that the inactivation of mast cells by the anti-inflammatory function of estrogen may account for the gender difference in the GERD spectrum. Other studies have described the contribution of female steroid hormones to the gender difference in these diseases. Estrogen is reported to modulate the metabolism of fat, and obesity is a main risk factor of GERDs. Moreover, estrogen could confer esophageal epithelial resistance to causative refluxate. These functions of estrogen might explain the approximately 20-year delay in the incidence of BE and the subsequent development of EAC in women compared to men, and this effect may be responsible for the male predominance. However, some observational studies demonstrated that hormone replacement therapy exerts controversial effects in GERD patients. Nevertheless, the estrogen-related endocrine milieu may prevent disease progression toward carcinogenesis in GERD patients. The development of innovative alternatives to conventional acid suppressors may become possible by clarifying the mechanisms of estrogen.

Keywords: Gastro-esophageal reflux disease, Barrett’s esophagus, Esophageal adenocarcinoma, Estrogen, Male predominance

Core tip: Gastro-esophageal reflux disease (GERD), Barrett’s esophagus and esophageal adenocarcinoma are epidemiologically recognized to be more prevalent in males due to an unknown mechanism. Our recent animal study revealed that estrogen contributes to the gender difference by inactivating inflammatory cells. Additionally, several studies demonstrated that estrogen confers epithelial resistance against causative refluxate and modifies adipose tissue metabolism in obese people and prevent the onset of GERDs. Consequently, the estrogen-related endocrine milieu in women could retard the progression of chronic inflammation to esophageal carcinogenesis, which is likely responsible for the predominance of GERD in males.