Biochemical mechanisms linking estrogen levels to Gastroesophageal Reflux Disease (GERD)

Gastroesophageal reflux disease (GERD)-A frequent gastro-esophageal manifestation that presents as the reflux of gastric contents into the esophagus causing symptoms such as heartburn and regurgitation; this is with and without some apparent mucosal injury. GERD is a significant burden in terms of the impaired ability to function in daily life, sleep quality, and overall quality of life, and it can develop a whole series of complications such as erosive esophagitis, Barrett's esophagus and esophageal adenocarcinoma. Notable sex-related differences in the presentation & outcome of GERD point to possible sex hormone, particularly estrogen, roles in the disease pathophysiology. Estrogen receptors are in fact present along the gastrointestinal tract including epithelial of the esophagus, lymphocyte, and smooth muscle suggesting that estrogen signaling may modulate both reflux mechanisms and the condition of tissues. The objective of this narrative review is to provide a summary of biochemical mechanisms through which the level of hormones and hormone signaling pathways affect the symptoms of GERD and associated complications. A thorough literature search was performed based on PubMed database search, focusing mainly on studies that have been published the last 10-15 years. Key search terms were GERD, estrogen, estradiol, estrogen receptors, nitric oxide, lower esophageal sphincter, hormone replacement therapy and pregnancy. Evidence from human and animal studies indicates that estrogen may have a beneficial effect on reflux episodes, because of the nitric oxide relaxation of the lower esophageal sphincter throwing out of balanced control of gastroesophageal reflux. On the other hand, estrogen seems to have protective effects in the esophageal mucosa by improving the epithelial barrier integrity by regulating tight junctions and modulating inflammatory responses. These dual and sometimes opposing actions point to the complexity of the role of estrogen in GERD pathogenesis. Further mechanistic human studies combining hormonal measures and formulations of objective reflux parameters, as well as mucosal injury, are required to elucidate the clinical importance and therapeutic implications of estrogen in the pathogenesis of GERD.