Cigarette Smoke Increases Progesterone Receptor and Homeobox A10 Expression in Human Endometrium and Endometrial Cells: A Potential Role in the Decreased Prevalence of Endometrial Pathology in Smokers1

Abstract

Cigarette smoking has long been tied to a multitude of poor health outcomes; however, in reproductive biology, smoking has shown several unintuitive findings. Smoking is associated with significantly decreased rates of endometriosis and endometrial cancer. Here, we show that treatment with cigarette smoke extract leads to increased mRNA and protein expression of homeobox A10 (HOXA10) and progesterone receptor (PGR) as well as more rapid decidualization of endometrial stromal cells in vitro. In vivo, mice exposed to cigarette smoke similarly showed increased expression of HOXA10 and PGR in the endometrium. Both HOXA10 and PGR drive endometrial differentiation and are suppressed in endometrial tumors and in endometriosis. The increased expression found upon exposure to cigarette smoke may provide a protective effect, mediating the decreased incidence of endometrial disease among smokers. This mechanism contrasts with the accepted paradigm that the effects of smoking on the uterus are secondary to ovarian alterations rather than direct effects on endometrium as demonstrated here.

Graphical Modeling of Gene Expression in Monocytes Suggests Molecular Mechanisms Explaining Increased Atherosclerosis in Smokers

“…It is expressed in the endothelium in a location-dependent manner, with lower expression in atheroprone than in atheroresistant arteries [31], [32]. HOXA10 expression in endometrium has been shown to be directly affected by cigarette-smoke extract both in humans and mice [33]. Therefore, there is support in the literature linking at least two genes of the network to smoking and plaques.…”

Associations between lifetime tobacco exposure with infertility and age at natural menopause: the Women's Health Initiative Observational Study

“…In addition, several studies have shown significant associations with SHS exposure and earlier age at menopause, both from physiological and population studies 9 11–15 35 38 39. A very early study in 1986 found such an association and brought out the necessity of using never-smoking women who have not been exposed to any SHS throughout life as a reference group 11.…”

Risk factors for endometrial cancer in black and white women: a pooled analysis from the epidemiology of endometrial cancer consortium (E2C2)

“…[33, 34] Cigarette smoking appears to increase circulating progesterone levels, and in vitro studies suggest it increases expression of progesterone receptors in endometrial stromal cells. [35, 36] Ever smoking women have also been shown to have lower ages at natural menopause compared to never smokers, and to be thinner. [37, 38] In 2011, 15.5% of adult black women and 18.8% of adult white women reported current smoking.…”