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Gender-Specific Protection of Estrogen against Gastric Acid-Induced Duodenal Injury: Stimulation of Duodenal Mucosal Bicarbonate Secretion

Departments of Medicine (A.S., C.C., K.H.K., J.C., X.D., H.D.) and Reproductive Medicine (H.-h.Z., D.-b.C.), School of Medicine, University of California San Diego, La Jolla, California 92093; and Department of Gastroenterology (B.T.), Zunyi Medical College, Zunyi, Guizhou 563003, People’s Republic of China

Address all correspondence and requests for reprints to: Hui Dong, M.D., Ph.D., Division of Gastroenterology, Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093. E-mail: h2dong{at}ucsd.edu; or Dong-bao Chen, Ph.D., Division of Maternal-Fetal Medicine, Department of Reproductive Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093. E-mail: dochen{at}ucsd.edu.

Because human duodenal mucosal bicarbonate secretion (DMBS) protects duodenum against acid-peptic injury, we hypothesize that estrogen stimulates DMBS, thereby attributing to the clinically observed lower incidence of duodenal ulcer in premenopausal women than the age-matched men. We found that basal and acid-stimulated DMBS responses were 1.5 and 2.4-fold higher in female than male mice in vivo, respectively. Acid-stimulated DMBS in both genders was abolished by ICI 182,780 and tamoxifen. Estradiol-17β (E₂) and the selective estrogen receptor (ER) agonists of ER [1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole] and ERβ [2,3-bis(4-hydroxyphenyl) propionitrile], but not progesterone, rapidly stimulated ER-dependent murine DMBS in vivo. E₂ dose dependently stimulated murine DMBS, which was attenuated by a Cl^–/HCO₃^– anion exchanger inhibitor 4,4'-didsothio- cyanostilbene-2, 2'-disulfonic acid, removal of extracellular Cl^–, and in cystic fibrosis transmembrane conductance regulator knockout female mice. E₂ stimulated murine DMBS in vitro in both genders with significantly greater response in female than male mice (female to male ratio = 4.3). ER and ERβ mRNAs and proteins were detected in murine duodenal epithelium of both genders; however, neither ER nor ERβ mRNA and protein expression levels differed according to gender. E₂ rapidly mobilized intracellular calcium in a duodenal epithelial SCBN cell line that expresses ER and ERβ, whereas BAPTA-AM abolished E₂-stimulated murine DMBS. Thus, our data show that E₂ stimulates DMBS via ER dependent mechanisms linked to intracellular calcium, cystic fibrosis transmembrane conductance regulator, and Cl^–/HCO₃^– anion exchanger. Gender-associated differences in basal, acid- and E₂-stimulated DMBS may have offered a reasonable explanation for the clinically observed lower incidence of duodenal ulcer in premenopausal women than age-matched men.