Adiposity alters protective mechanisms of progesterone through dysregulation of endometrial metallothionein expression

In this study, we sought to understand the effects of excess adipose on the benign endometrium. We used a physiologic in vitro coculture system consisting of multicellular organoids of the benign human endometrium and adipose spheroids in the presence of estradiol, progesterone, and testosterone to mimic the menstrual cycle. Gene expression analysis of endometrial organoids under high adiposity conditions revealed downregulation of genes normally expressed in secretory endometrium, suggestive of an altered progesterone response. Genes associated with ion homeostasis and detoxification of reactive oxygen species were also downregulated, including the metallothionein (MT) family of genes. We demonstrated that MT gene expression in endometrial organoids was regulated by progesterone specifically in the epithelial cells, and that progesterone receptor is recruited to the promoters of MT genes in endometrial epithelial cells. We illustrated the impact of MT dysregulation by silencing MT genes in endometrial epithelial cells, resulting in increased DNA damage. Our results reveal that exposing the endometrium to high adiposity can compromise the protective effects of progesterone, dysregulate MT genes in the endometrial epithelium, and leave the endometrium vulnerable to ROS-induced DNA damage.