The Effect of Copper on Endometrial Receptivity and Induction of Apoptosis on Decidualized Human Endometrial Stromal Cells

Abstract

Intrauterine devices (IUDs) have been widely used to prevent pregnancies with great efficacy during decades. It has been demonstrated that IUD alters the endometrial gene expression, but there is no scientific data about how copper, a metal commonly used in these devices, by itself, is able to influence the processes of endometrial receptivity and apoptosis in decidualized human endometrial stromal cells. Five endometrial samples were obtained from fertile women and processed by a standard protocol to obtain human endometrial stromal cells for in vitro studies. Stromal cells were cultured in vitro and decidualized for 8 days. At day 6, copper was added to the treatment group or camptothecin as positive control for apoptosis until day 8. Five endometrial samples were used in each group. The aim of this study was to analyze the effect of copper in apoptosis and necrosis by flow cytometry, to visualize the apoptotic microtubule network during apoptosis by immunofluorescence, and finally to determine the gene expression profile of a panel of 192 genes related to endometrial receptivity and immune system by quantitative reverse transcription PCR (RT-qPCR). Copper, compared to the decidualized group, induced changes in the gene expression by an order of magnitude in 49 genes (42 up- and 9 downregulated). This alteration in the decidualization gene signature by copper includes 19 genes involved in the endometriosis pathology and others related to other gynecological disorders such as preeclampsia and infertility. Our results indicate that copper does not increase the apoptosis level induced by the decidualization treatment. However, copper alters the gene expression of some biomarkers of endometrial receptivity and immune response.

Clinical Evaluation of Li Brush Endometrial Samplers for Diagnosing Endometrial Lesions in Women With Intrauterine Devices

“…The characteristics of foreign-body reaction are a significant increase in the number of neutrophils, monocytes, and plasma cells (30). For Cu-IUDs, the copper released from the IUD is oxidized by enzymes and then dissolved by the amino acids in the endometrial fluid, which alters the endometrial receptivity and immune response (31) and influences the metabolism of endometrial cells (30). In addition, Cu-IUDs induce cytokine production to aggregate immune cells in the endometrium, strengthening the inflammatory response (32,33).…”

Levonorgestrel IUD: is there a long-lasting effect on return to fertility?

“…There is no effect on follicular development or ovulation 25 . While there are no in vivo studies specifically evaluating the effect of the copper IUD on the endometrium at the molecular level, Carrascosa et al demonstrated that addition of copper to decidualized human endometrial stromal cells (dHESCs) in vitro disrupts the gene signature associated with endometrial receptivity 26 , thus suggesting that impairing endometrial receptivity can be part of the mechanism of action of the copper IUD.…”

Size dependent inhibition of sperm motility by copper particles as a path towards reversible male contraception

“…These showed no increase in endometrial tissue after exposure to Copper IUDs and is thus considered safe. 34 Disadvantages include disruptions in the menstrual cycle and post-surgical pain and bleeding and implantation involves a small surgery. Therefore, this method is not widely recommended for all women.…”