Association Between Circulating Levels of Sex Steroid Hormones and Barrett’s Esophagus in Men: A Case–Control Analysis

Abstract

Background & Aims Esophageal adenocarcinoma is believed to result from the progression of gastroesophageal reflux disease to erosive esophagitis and re-epithelialization of the esophagus with a columnar cell population termed Barrett's esophagus (BE). Men develop BE and esophageal adenocarcinoma more frequently than women, and the ratio is increasing; approximately 7 men are diagnosed with malignancy for every woman, yet little is known about the mechanisms of this difference. We assessed whether sex steroid hormones were associated with BE in a male population. Methods We analyzed data from the Barrett's Esophagus Early Detection Case Control Study, based at the Walter Reed National Military Medical Center. Blood samples were collected from 173 men with BE and 213 men without BE (controls, based on endoscopic analysis); 13 sex steroid hormones were measured by mass spectrometry and sex hormone binding globulin was measured by ELISA. We also calculated free estradiol, free testosterone and free dihydrotestosterone (DHT). We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age, race, smoking status, alcohol consumption, body mass index (BMI; kg/m2), heartburn, regurgitation, and gastroesophageal symptom score (excluding heartburn and regurgitation). Results Levels of free testosterone and free DHT were positively associated with BE risk; patients in the highest quartile for these hormones were most likely to have BE (for free testosterone, OR=5.36; 95% CI, 2.21–13.03; P=0.0002 and for free DHT, OR=4.25, 95% CI, 1.87–9.66; P=.001). Level of estrone sulfate was inversely associated with BE risk (P for trend=.02). No other hormone was associated with BE risk. Relationships were not modified by age or BMI. Conclusions In an analysis of men, levels of free testosterone and free DHT were significantly associated with risk of BE.

A global assessment of the male predominance in esophageal adenocarcinoma

“…The existing evidence regarding a potential association between estrogen exposure and risk of EAC or its precancerous lesion, Barrett's esophagus, remains inconclusive, however [2, 5, 8]. Based on the hypothesized protective role of estrogenic exposures, the increased male-to-female ratios over time observed in several populations included in this study may be partially explained by the increasing use of oral contraceptives and hormonal replacement therapy [22], which may have resulted in a decrease of EAC risk in women in these countries.…”

“…The male predominance is not readily explained by sex differences in the exposure to the established risk factors for EAC, i.e., obesity, gastroesophageal reflux disease, Helicobacter pylori ( H. pylori ) infection (inverse association) or tobacco smoking [2, 5, 7]. Instead, it has been hypothesized that sex hormones and reproductive factors might play a role in the development of EAC or its precancerous lesion Barrett's esophagus, although the existing evidence is far from conclusive [2, 5, 8]. …”

Epidemiology, Diagnosis, and Management of Esophageal Adenocarcinoma

“…9 Among men, circulating levels of free testosterone and free dihydrotestosterone are strongly associated with Barrett’s esophagus (adjusted ORs for 4 th vs 1 st quartile, 5.36; 95% CI, 2.21–13.0 and OR, 4.25; 95% CI, 1.87–9.66, respectively). 65 Among women who have had children, breast feeding is inversely associated with the risk of EAC, suggesting hormone effects. 66 But no association among women has been found for the number of children, age of menarche or menopause, or use of hormone replacement therapy or oral contraceptives.…”

Obesity and the Incidence of Upper Gastrointestinal Cancers: An Ecological Approach to Examine Differences across Age and Sex

“…Furthermore, breastfeeding has been found to decrease the risk for esophageal and gastric junction adenocarcinoma (46). In males, levels of free testosterone and dihydrotestosterone have been positively associated with an increased risk of Barrett’s esophagus (47). The fact that total testosterone levels decrease with age and have been shown to be negatively related with obesity (48) is in line with our observation that sex disparities for both types of esophageal cancer were most pronounced at younger ages and progressively decreased after age 65 years - as opposed to sex differences in gastric cancer incidence, which increased until age 60 years before levelling off.…”