|Ahead of print publication
Effects of copper-containing intrauterine devices on the endometrium
Jia-Hui Che, Xiao-Ying Yao
Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
|Date of Submission||08-Jun-2020|
|Date of Decision||06-Aug-2020|
|Date of Acceptance||08-Oct-2020|
|Date of Web Publication||19-Feb-2021|
Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011
Source of Support: None, Conflict of Interest: None
The use of copper-containing intrauterine devices (Cu-IUDs) is a safe, effective, and long-term contraceptive method. Here, we review the effects of Cu-IUDs on subsequent pregnancy and the morphology, local coagulation function, sensitivity to estrogen and progesterone, cell proliferation, and immune response of the endometrium. Studies on the morphology of endometrium indicate that the use of Cu-IUDs can affect the number and binding capacity of estrogen and progesterone receptors in the endometrium and reduce the response of the endometrium to estrogen and progesterone. The use of Cu-IUDs can also affect the proliferation of endometrial cells, suggesting that the aseptic inflammation caused by Cu-IUDs may differ from chronic infectious or noninfectious inflammation; this highlights that the use of Cu-IUDs provides protection against endometrial proliferative diseases. The use of Cu-IUDs increases local endometrial angiogenesis, bleeding tendency, and fibrinolytic activity, which can result in prolonged menstruation or abnormal uterine bleeding. Additionally, the use of Cu-IUDs can cause the infiltration of numerous lymphocytes, monocytes, macrophages, and other inflammatory cells around the endometrial gland and changes in endometrial immune function, immune cell function, and the number and type of immune molecules. Cu-IUD-induced decidual injury significantly increases the invasiveness of trophoblasts, further affecting the aberrant expression of their growth-, angiogenesis-, and invasion-related factors and improving the formation of the placenta. Moreover, the endometrial damage caused by Cu-IUD placement before embryo transfer can improve both clinical pregnancy and live birth rates; however, specific changes in the immune system after Cu-IUD use as well as its effects on future pregnancies require further investigation.
Keywords: Contraception; Copper; Endometrium; Intrauterine Contraception; Intrauterine Device
| Introduction|| |
The use of intrauterine devices (IUDs) is a safe, practical, simple, economical, and reversible contraceptive method. Compared with levonorgestrel intrauterine delivery system, copper-containing IUDs (Cu-IUDs) are safe, are of low cost, and have low pregnancy and dropout rates; therefore, they are widely used in clinical settings. However, initially after the placement of Cu-IUDs, copper ions are released which may cause menorrhagia, and a small number of users may experience side effects such as lumbar pain, abdominal pain, and abnormal uterine bleeding. Many studies have examined the use of Cu-IUDs, however a comprehensive summary about it remains lacking. This review summarizes the existing literature and provides prospects for future research.
| Clinical Application and Effects of Copper-Containing Intrauterine Devices|| |
Currently, IUDs are the most commonly used reversible contraceptive devices worldwide, and Cu-IUDs are one of the main types of IUDs. Contraception using Cu-IUDs depends on the toxicity of copper ions to spermatozoa and embryos. The use of Cu-IUDs has become a standard intrauterine contraception owing to its long-term effectiveness, safety, and economic value; however, for some women, the use of Cu-IUDs causes side effects, including increased menstruation and dysmenorrhea, which can affect their quality of life and increase the removal rate of Cu-IUDs. Composite Cu-IUDs,,, such as those comprising copper/low-density polyethylene/methyl vinyl silicone rubber and copper/low-density polyethylene nanocomposites, are currently undergoing animal and clinical trials. If composite Cu-IUDs can significantly minimize or eliminate side effects, such as menstrual changes and irregular uterine bleeding, caused by the use of traditional IUDs, the utilization rate of Cu-IUDs would markedly improve.
| Effects of Copper-Containing Intrauterine Devices on the Morphology of Endometrial Glands and Stroma|| |
Previous studies have shown that the presence of Cu-IUDs induces morphological changes in the local endometrium that are mainly manifested by a decrease in endometrial hyperplasia or an increase in endometrial atrophy owing to the oxidation and dissolution of copper in the uterine cavity. Copper ions are mainly localized in the nucleus, mitochondria, and cytosol of endometrial cells and exert antagonistic effects against zinc ions in the endometrium, thus inhibiting the activity and periodicity of zinc-containing carbonic anhydrase and alkaline phosphatase while enhancing the activity of lysosomal enzymes.
Gu et al. reported that the long-term use of Cu-IUDs is linked to a decrease in the number of glands in the endometrium. Other studies have demonstrated that after 10 years of Cu-IUD placement, the development and maturation of endometrial epithelial cells was inhibited and delayed, respectively, whereas the development of stroma was improved or delayed, indicating an inconsistent development of glands and stroma., Rupture of organelles, swelling of mitochondria and medullary corpuscles, dilatation and degranulation of the endoplasmic reticulum, increase in lysosome number, and the disappearance of nucleolar tube system were also observed in the endometrial cells at the attachment site of Cu-IUDs., Moreover, under the influence of copper ions, the secretory peak of alkaline phosphatase is delayed, and alkaline phosphatase level gradually decreases. The physiological effect of copper ions on glycogen decomposition also changes accordingly, resulting in abnormal glycogen metabolism. Morphologically, the distribution of intracellular glycogen particles becomes abnormal, the intracellular glycogen levels increase significantly in the proliferative phase (cycle days 7–14), and a large area of glycogen plaques appears. In contrast, intracellular glycogen levels decrease in the secretory phase (cycle days 15–28), especially in the early secretory stage (cycle days 15–19), and glycogen plaques in the secretory cells of the glandular epithelium are absent.
The above findings indicate that Cu-IUD use can reduce the number of endometrial glands and inhibit the development of epithelial cells; however, there is currently no evidence indicating that Cu-IUD use induces endometrial hyperplasia, and this suggests that the use of Cu-IUDs provides protection against endometrial proliferative diseases.
| Effects of Copper-Containing Intrauterine Devices on the Sensitivity of the Endometrium to Estrogen and Progesterone|| |
Many studies have shown that the use of Cu-IUDs does not affect the levels of estrogen and progesterone in human and animal serum;,, however, Fahmy et al. reported that serum estrogen levels in Cu-IUD users in the mid-luteal phase were lower than those in inert IUD users. With respect to estrogen, Cu-IUDs reduce the number of estrogen receptors (ERs) in the endometrial glands at contact sites but do not significantly change the sensitivity of the endometrium to estrogen. Contrastingly, although the use of Cu-IUD does not significantly change the number of progesterone receptors (PRs) in endometrial glands, it reduces the sensitivity of the endometrium to progesterone. Guleria et al. reported concentration changes in ERs and PRs in the endometrial gland during continuous Cu-IUD use. Tamaya et al. performed animal studies and found copper as a competitive inhibitor for steroid receptor binding. Copper ions released from Cu-IUDs directly interfere with the binding of estrogen and progesterone to their corresponding receptor-binding sites, and PRs are more affected by copper ions than ERs. For example, Nutting and Mueller found that copper ions released from Cu-IUDs locally block the effect of progesterone but not the effect of estrogen on the endometrial structure of the epithelial tissue.
These findings suggest that Cu-IUD use can affect the number and binding capacity of ERs and PRs in the endometrium, which can in turn reduce the response of the endometrium to estrogen and progesterone. In addition, this may partially explain the poor efficacy of estrogen and progesterone in the treatment of irregular bleeding during the use of Cu-IUDs.
| Effects of Copper-Containing Intrauterine Devices on the Proliferation of Endometrial Cells|| |
The use of Cu-IUDs decreases nucleic acid metabolism in local endometrial cells, thus affecting the DNA content in the nucleus. In addition, it decreases the mitotic activity of endometrial cells and delays local epithelial development. Grundsell observed that Cu-IUD use significantly decreased the total amount of DNA in animal and human endometrium during the first trimester of pregnancy, during which this amount should have normally increased. Zhang et al. reported the ultrastructure of the endometrium of women who used Cu-IUDs for >10 years and observed that the use of Cu-IUDs inhibits DNA synthesis in the nucleus of the endometrium and prolongs the S phase of proliferative endometrial cells. Therefore, we speculated that the use of Cu-IUDs delays the development of epithelial cells and inhibits cell maturation, which is further suppressed by intercellular edema. Moreover, Kamal and Hafez reported that Cu-IUD use for 9 months results in significantly decreased proliferative activity and mitotic index of endometrial glands. Recent studies have shown that the use of Cu-IUDs causes neither an abnormal metabolism in local endometrial cells nor mutations in tumor suppressor genes. Although nucleic acid metabolism is affected by Cu-IUD use, some studies have reported that the use of Cu-IUDs does not increase the expression of ki-67, P16, p53, and K-ras genes in human local endometrial cells.,, In addition, numerous clinical studies and meta-analyses have shown that the use of Cu-IUDs does not increase the risk of endometrial lesions, and this risk does not vary considerably with respect to the number of years the Cu-IUDs are used.,
Previous studies have suggested that chronic local inflammation may cause a predisposition of endometrial cells to tumor development by damaging DNA and inducing cell proliferation, which can initiate and promote neoplastic transformation., A pro-inflammatory environment can also increase the production of estrogen; the pathophysiology of endometrial carcinoma caused by chronic inflammation may not be directly related to increased estrogen production., The use of Cu-IUDs does not affect the expression of intracellular tumor suppressor genes; however, it affects the development of uterine glandular epithelial cells.,,,, Therefore, the use of Cu-IUDs provides protection against endometrial cancer. These findings suggest that the aseptic inflammation caused by the use of Cu-IUDs is different from chronic infectious or noninfectious inflammation.
| Effects of Copper-Containing Intrauterine Devices on Endometrial Angiogenesis and Local Coagulation Function|| |
The use of Cu-IUDs increases local endometrial angiogenesis, bleeding tendency, and fibrinolytic activity, all of which may result in prolonged menstruation and/or abnormal uterine bleeding [Figure 1]. Zhang et al., using microscopy, observed the appearance of capillary microthrombus in endometrial stroma, increased blood vessel density in the endometrial functional layer, and dilation of local blood vessels in women who used Cu-IUDs for 10 years. Pan et al. found that the use of Cu-IUDs caused abnormal bleeding in the endometrium, as evidenced by the degeneration and dilatation of spiral arteries, especially in the cavernous layer. This indicates that abnormal uterine bleeding may be associated with a decreased contractile function of spiral arteries. In addition, the use of Cu-IUDs for 3 months has been reported to reduce the expression of tissue inhibitor of metalloproteinases and increase the expression of matrix metalloproteinase in the endometrium; these physiological events can lead to collagen degradation of the basement membrane of endometrial vessels and result in vascular lesions, rupture, and bleeding. Moreover, the use of Cu-IUDs for 1 month has been reported to increase the expression of vascular endothelial growth factor (VEGF), VEGF messenger RNA (mRNA), and VEGF receptors in women with abnormal uterine bleeding., VEGF expression is positively correlated with blood vessel density, and an increase in the expression of VEGF can cause an increase in endometrial blood vessel density and result in increased menstruation or abnormal uterine bleeding. In contrast, Coskun et al. reported that during the use of Cu-IUDs for 1 to 3 months, the release of copper ions from Cu-IUDs promotes the production of cyclooxygenase (COX2) in the local endometrium. COX2 catalyzes the production of prostaglandin E2, which in turn causes local hypoxia in the endometrium and decreases the pulsation and resistance indexes of local endometrial arteries; this can lead to abnormal uterine bleeding. The effects of Cu-IUD use on local fibrinolytic systems are mainly reflected by the possibility of an increased and decreased expression of plasminogen activator and plasminogen activator inhibitor-1, respectively, in local animal tissues., This can eventually lead to the accentuation of fibrinolytic activity and hemorrhage. The increased expression of substance P (SP) and SP receptor has also been found in animal studies; this increased expression may affect the contractile force of the myometrium and uterine blood flow. In contrast, the use of Cu-IUDs for 3 to 6 months can also reduce the activity of factor VIII in the local endometrium and increase bleeding tendency.
|Figure 1: Summary of the effect of Cu-IUD on endometrial angiogenesis and local coagulation function. VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; COX2: Cyclooxygenase-2; PEGE2: Prostaglandin E2; MMP: Matrix metalloproteinase; TIMP-1: Tissue inhibitor of metalloproteinases-1; TPA: Plasminogen activator; PAI-1: Plasminogen activator inhibitor-1; SP: Substance P; SP-R: Substance P receptor; FVIII: Factor VIII; Cu-IUD: Copper-containing intrauterine device.|
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| Effects of Copper-Containing Intrauterine Devices on the Endometrial Immune System|| |
Changes in immune cells after copper-containing intrauterine device use
Several studies have reported that the use of Cu-IUDs can cause the infiltration of a large number of lymphocytes, granulocytes, monocytes, macrophages, mast cells, and other inflammatory cells in the endometrial gland.,,, Sheppard reported that Cu-IUD use facilitates the migration of polymorphonuclear leukocytes and macrophages from the stroma into the uterine cavity and that leukocyte migration is greater during Cu-IUD use than during inert IUD use. Furthermore, Dong reported that the number of CD8+ lymphocytes increases with use, whereas the number of CD4+ lymphocytes decreases, suggesting that the long-term use of Cu-IUDs may enhance immunosuppressive activity. Achilles reported that the use of Cu-IUDs decreases the expression of CCR5 human immunodeficiency virus co-receptor on the endometrium and cervical T cells; this phenomenon suggests that the use of Cu-IUDs does not increase the sensitivity to HIV infection.
Changes in immune cytokines after copper-containing intrauterine device use
The use of Cu-IUDs affects the concentration of some cytokines and the expression of cytokine mRNA in the endometrium. A previous study has shown that the concentration of total immunoglobulin (Ig) and IgG in the endometrium of Cu-IUD users has significantly increased, whereas the concentration of leukemia inhibitory factor, interleukin (IL)-2, and sIgA has decreased., In another study, the use of Cu-IUDs increased the average levels of IL-1β, IL-6, and tumor necrosis factor-α mRNA in the late secretory phase of menstruation. Moreover, in a study wherein a morphological evaluation of endometria exposed to Cu-IUDs was performed, the infiltration of numerous granulated lymphocytes and macrophages was observed; this infiltration may explain the changes in cytokine and mRNA expression in the endometria. The enhanced production and cytotoxic effects of cytokines may be considered a mechanism that contributes to the antifertility effects of Cu-IUDs.
Only a few studies have investigated Cu-IUD-induced changes in endometrial immune function, including the type, number, and function of immune cells as well as the number and types of immune molecules. Mechanistic studies are required such that the effects of the use of Cu-IUDs can be further elucidated.
| Effects of Copper-Containing Intrauterine Devices on Future Pregnancies|| |
At present, the effect of Cu-IUD use on the future pregnancies of women remains controversial. Some integrins are expressed periodically in the endometrium during embryo implantation and can be used as markers of endometrial receptivity. A previous study has shown that the use of Cu-IUDs for more than 3 years results in the reduced expression of αv, α3, and β1 integrins and inhibits the binding of these integrins to the extracellular matrix, subsequently resulting in the suppression of implantation. In contrast, Cu-IUD-induced decidual injury significantly increases the invasiveness of trophoblasts, which further affects the abnormal expression of growth-, angiogenesis-, and invasion-related factors in trophoblast populations, including VEGF, epidermal growth factor receptor, and c-erbB-2 oncoprotein,, thus improving the formation of the placenta. In addition, the endometrial damage caused by the use of Cu-IUDs before embryo transfer can improve clinical pregnancy and live birth rates,,,, and studies have shown that using Cu-IUDs for two menstrual cycles can increase implantation and pregnancy rates in women who have experienced repeated implantation failure. In addition, the use of Cu-IUDs reduces the risk of pre-eclampsia during pregnancy, as demonstrated in a case–control study. Consequently, a certain level of decidual injury caused by the use of Cu-IUDs increases the invasion potential of trophoblasts to maternal spiral arteries, a process that is linked to pre-eclampsia when the uterine spiral artery is inadequate or incomplete. The specific mechanisms underlying the effects of Cu-IUDs on the incidence of pre-eclampsia remain to be elucidated.
| Conclusion|| |
The use of Cu-IUDs can reduce the incidence of endometrial cancer and potentially improve the success rate of future pregnancies or placenta formation through its effects on the endometrium. However, the use of Cu-IUDs can also cause side effects such as increased menstruation. The specific mechanisms underlying the effects of Cu-IUDs on the endometrium, changes in immune system after Cu-IUD use, and effects of the use of Cu-IUDs on future pregnancies require further investigation.
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Conflicts of interest
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