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

Abstract

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-17beta (E2) and the selective estrogen receptor (ER) agonists of ERalpha [1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole] and ERbeta [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). ERalpha and ERbeta mRNAs and proteins were detected in murine duodenal epithelium of both genders; however, neither ERalpha nor ERbeta mRNA and protein expression levels differed according to gender. E2 rapidly mobilized intracellular calcium in a duodenal epithelial SCBN cell line that expresses ERalpha and ERbeta, 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.

Molecular Mechanisms of Calcium-sensing Receptor-mediated Calcium Signaling in the Modulation of Epithelial Ion Transport and Bicarbonate Secretion

“…All experiments were performed with adult Harlan C-57 black mice; homozygous CFTR knockout (CFTR Ϫ/Ϫ ) mice and their wild-type littermates (CFTR ϩ/ϩ ), which were established as described previously (13); and mice deficient in KCNQ1 (kcnq1 Ϫ/Ϫ ) and their wildtype littermates (kcnq1 ϩ/ϩ ), which were generated as described earlier (14).…”

“…We found that although cyclic AMP plays a major role in intestinal Cl Ϫ secretion, Ca 2ϩ signaling may be critical for transepithelial HCO 3 Ϫ secretion (13). However, activation of most well defined receptors expressed in intestinal epithelial cells usually increase both [Ca 2ϩ ] cyt and intracellular cyclic AMP levels, making it difficult to distinguish between [Ca 2ϩ ] cyt -and cyclic AMP-regulated epithelial ion transports.…”

Traumatic Brain Injury and the Gastrointestinal Tract: The Role of Female Sexual Hormones

“…Also, previous studies have shown that peptic ulcer is more common in men than women. Therefore, it is rational to infer that, similar to other organs, E2 and progesterone may have protective effects in GI tract, and E2 plays a protecting role against acid-peptic duodenal injury in females [47]. Steroid hormones, in particular progesterone and estrogen, have effects on the gastric motility and secretions [19], and are also involved in the pathogenesis of some functional disorders in the gut [20].…”

“…Studies have shown that pregnant women or women taking oral contraceptive pills (estrogen/progesterone compounds) exhibited a reduced frequency of duodenal ulcer [73]. Furthermore, duodenal ulcer runs a more serious course in postmenopausal than premenopausal women [47]. Finally, clinical observations showing that pregnant women with high estrogen levels of placental origin hardly develop ulcers and women taking oral contraceptives experience a significantly decreased incidence of ulcers [73], strongly support the protective role of estrogen in the duodenum [3].…”

“…Some of the possible mechanisms underlying the activity of these hormones against ulcerative effects of traumatic brain injuries are: maintaining calcitonin gene relevant peptide (CGRP) level, that has the protective role in mucosal injuries [96], over-production of mucosal secretion by gastric mucosal [17], the increase of bicarbonate secretion from gastric mucosal like to the increased secretion of bicarbonate from duodenum mucosal by estrogen [47], alteration of hypothalamic pituitary axis (HPA) is response to stress [86], the reduction of vascular epidermal growth factor (VEGF) secretion in stomach [97], inhibition of oxidative stress [98], modulation of nitric oxide (NO) production [99], regulation of autonomic nervous system activity [100], interaction with melatonin in gastric mucosal level [101], promotion of angiogenesis [102], reduction of gastric inflammation by decreasing TNF-α release [103], and inhibition of apoptosis due to ischemia [104].…”