In uterine endometrium, estrogen induces proliferation without differentiation. Progesterone, through its activation of PGR, inhibits the action of estrogen, preventing proliferation and triggering differentiation. Similarly, HOXA10 induces endometrial differentiation. In both endometrial cancer and endometriosis, expression of HOXA10 and PGR is reduced. Thus, the increase in expression of these two genes and the more rapid decidualization in response to exposure to cigarette smoke may provide the protective effects that prevent the development of these proliferative diseases in women who smoke.
One commonly accepted theory for the reduced incidence of endometrial cancer among smokers is that smoking causes ovarian damage, diminished ovarian reserve, and decreased estrogen production. Endogenous or exogenous estrogens unopposed by progesterone can increase the mitotic activity in endometrial cells [20
], leading to hyperplasia and malignancy [21
]. However, even lower-than-average levels of estrogen can cause hyperplasia or cancer as seen in women with chronic anovulation and low but static estrogen levels. Similarly, menopausal women treated with estrogen in the absence of a progestin have a high incidence of endometrial hyperplasia despite estrogen exposure well below that of a reproductive-age woman [22
]. It is unlikely that the small decline in estrogen production seen in reproductive-age smokers will prevent hyperplasia. Treatment with exogenous progesterone has been shown to have protective effects against development of endometrial cancer, as seen in the decreased incidence of endometrial cancer among users of combined estrogen and progestin oral contraceptives [23
]. An increase in the expression of PGR in the endometrium of smokers may provide a protective effect against neoplasm by creating increased progesterone sensitivity and responsiveness. We speculate that increased PGR may also enhance endometrial development and explain the high pregnancy rate among young smokers before the onset of diminished ovarian reserve.
Likewise, lower HOXA10 expression has been correlated with increased tumor grade in endometrial carcinomas [24
]. Moreover, methylation of the HOXA10
promoter has been found to lead to decreased expression and is associated with endometrial tumors [14
]. Thus, the increased HOXA10 expression in the uterus upon exposure to cigarette smoke could confer a protective effect against the development of endometrial cancer, opposing the downregulation of this protein because of methylation.
Women with endometriosis have been shown to have decreased levels of HOXA10 in their ectopic and eutopic endometrium [13
]. Downregulation of HOXA10 may be required to decrease differentiation and allow the increased proliferation necessary for the development of endometriosis. As in endometrial cancer, hypermethylation of the gene is associated with diminished differentiation of endometrial cells, leading to endometriosis [26
]. Cigarette smoke-induced increases in uterine HOXA10 expression could counter the effect of methylation on the HOXA10
promoter and provide a protective effect against the development of endometriosis in women who smoke. HOXA10 drives increased differentiation and also preserves endometrial receptivity; the increase may impede the development of endometriosis while still allowing embryo implantation.
Expression of PGR is also decreased in women with endometriosis. Specifically women with endometriosis have decreased expression of PGR-B, one of two isoforms of PGR, in both the ectopic and the eutopic endometrium [29
]. Progesterone resistance is a prominent feature of this disease [30
]. The increased PGR driven by tobacco use may similarly increase progesterone action and protect against the development of endometriosis.
Although cigarette smoke appears to provide protection against endometriosis and endometrial cancer, its numerous other deleterious effects found both in the reproductive system and elsewhere certainly prohibit the recommendation that any woman smoke. Instead, the present study seeks to establish the molecular mechanism explaining the seemingly paradoxical observation that smoking decreases the incidence of these two diseases. Perhaps among the over 4000 compounds found in cigarette smoke is one or more that can prevent endometrial proliferation and induce the expression of genes that direct endometrial differentiation. Isolation and characterization of these compounds may lead to the development of novel therapeutic agents.