Abstract
Colorectal cancer (CRC) is the second cause of cancer-related death in both sexes worldwide. As pre-menopausal women are less likely to develop CRC compared to age-matched men, a protective role for estrogens has been hypothesized. Indeed, two isoforms of nuclear estrogen receptors (ER) have been described: ERα and ERβ. While the binding of 17beta-estradiol to ERα activates anti-apoptotic pathways, the interaction with ERβ activates caspase-3, inducing apoptosis. In this regard, several pieces of evidence show that ERβ tends to be under-regulated in advanced adenomas and CRC, with an opposite trend for ERα. Furthermore, ERβ stimulation slows adenomatous polyp growth and modulates relevant CRC pathways. Based on such considerations, dietary modulation of ER is promising, particularly in subjects with genetic predisposition for CRC. Nevertheless, the main limitation is the lack of clinical trials on a large population scale.
Highlights
IntroductionDespite recent advances in screening and treatment, colorectal cancer (CRC) remains the second most common cause of cancer-related death in both sexes worldwide
The Burden of Colorectal Cancer (CRC) and Epidemiology in WomenDespite recent advances in screening and treatment, colorectal cancer (CRC) remains the second most common cause of cancer-related death in both sexes worldwide
Weyant et al demonstrated a protective role of endogenous estrogen through upregulation of ERβ and a downregulation of ERα in the ApcMin/+ mice model; in their study, ovariectomized Min/+ mice with E2 supplementation had an equal number of tumors as littermates that were neither castrated nor supplemented with hormone replacement [43]
Summary
Despite recent advances in screening and treatment, colorectal cancer (CRC) remains the second most common cause of cancer-related death in both sexes worldwide. Especially estrogen, has been proposed as a possible explanation for this gender-based difference, especially in relation to the different CRC risk seen in pre-menopausal versus post-menopausal women. The fall of estrogen levels seen in post-menopausal women may apparently explain the worse overall survival seen in this cohort compared to age-matched men after the diagnosis of metastatic CRC [7]. Similar findings were revealed following inflammatory bowel disease patients for 10 years: men had a 60% higher risk of developing CRC compared to women [8], suggesting a possible role of estrogen as a modulator of inflammation-related carcinogenesis. Hormone replacement therapy may reduce the risk of CRC, as evidenced recently in a Swedish study, with a reduction of about 25% for current estradiol and estriol users [9]
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