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Changes in copper and zinc serum levels in women wearing a copper TCu-380A intrauterine device
Abstract
Objective To assess the effects of the copper intrauterine device (IUD) TCu-380A, on copper and zinc serum levels. Material and methods This longitudinal study enrolled 121 women attending Health Centres in Tehran between November 2011 and August 2012. A blood sample was obtained before use and three months after insertion of a TCu-380A IUD. Serum levels of copper and zinc were measured for the 101 women who had completed three months with the device in situ. Analyses of change included paired t-tests, McNemar tests and linear regression. Results Significant elevations in mean serum levels were found for both copper (170.22 μg/dl at three months vs.160.40 μg/dl at baseline, p = 0.034) and zinc (107.67 μg/dl at three months vs. 94.61 μg/dl at baseline, p < 0.001) three months after IUD insertion. Conclusions A slight, but significant increase in copper serum levels, not reaching toxic levels, was observed three months after TCu-380A IUD insertion. Zinc levels too had risen significantly, which was quite unexpected, and warrants further investigation.
... Furthermore, elevated serum Cu 2 + concentrations in the CG Cu and UFG Cu groups were detected in the rats at the early stage after implantation and much reduced amount of Cu 2 + in serum was found for the rats with UFG Cu-0.4Mg. Previous study had also exhibited that women with the TCu380A IUD displayed significant increase of Cu 2 + in serum, not reaching toxic criteria three months after TCu-380A IUD insertion [64] . It was reported that a conserved mechanism of Cu tolerance is metal sequestration by metallothioneins (MTs) [65] . ...
Copper intrauterine device is one of the most adopted contraceptive methods with high effectiveness (over 99 %), low cost, spontaneous reversibility and long-lasting usage. However, the side effects induced from the initial burst release of copper ions (Cu²⁺) hinder the continuation of the Cu-IUD made of Coarse-Grained Copper (CG Cu). We proposed to tailor the bio-corrosion behaviors of better control of Cu²⁺ release via the addition of bioactive Mg into the ultrafine grained bulk Cu. Thus, Ultra-Fine Grained (UFG) bulk Cu with 0.4 wt.% Mg was produced via equal-channel angular pressing. The microstructures of the UFG Cu-0.4Mg was observed using electron backscatter diffraction and transmission electron microscopy techniques. The in vitro long-term corrosion behaviors in simulated uterine fluid, cytotoxicity to four cell lines, in vivo biocompatibility and contraceptive efficacy were all studied on CG Cu, UFG Cu and UFG Cu-0.4Mg materials. The results demonstrate that both the effect of ultrafine grains and the addition of bioactive Mg into Cu contribute to the suppression of the burst release of Cu²⁺ in the initial stage and the maintenance of high level Cu²⁺ in long-term release. Moreover, the UFG Cu-0.4Mg also exhibited much improved cell and tissue biocompatibility from both the in vitro and in vivo evaluations. Therefore, the contraceptive efficacy of UFG Cu-0.4Mg is still maintained as high as the CG Cu and UFG Cu while the side effects are significantly eased, suggesting the high potential of the UFG Cu-0.4Mg alloy as a new upgrading or alternative material for Cu-IUD.
Statement of significance
: The side effects from burst release of Cu²⁺ at the initial implantation stage of Cu-containing intrauterine devices (Cu-IUD) is one of the main drawbacks of these devices. In this work, an ultra-fine-grained Cu (UFG Cu) alloyed with a low amount of bioactive Mg was used for a Cu-IUD. The UFG Cu-0.4Mg alloy exhibited suppressed burst release of Cu²⁺ at initial implantation, while active Cu²⁺ release for long-term usage was maintained, comparable to coarse-grained pure Cu. Furthermore, the UFG Cu-0.4Mg alloy displayed significantly improved biocompatibility with human uterus cells and a much decreased inflammatory response within the uterus. Therefore, the side effects from Cu-IUD were eased, while high antifertility efficacy of the UFG Cu-0.4Mg alloy was maintained. The UFG Cu-0.4Mg alloy is promising for Cu-IUD.
... Considering the severe conditions in this experiment, the clinical use of Cu-IUD is deemed safe. However, the increased leucocytosis warrants further investigation to ascertain the long-term safety of the Cu-IUD in clinical use [23,24]. ...
Background
The aim of this study was to evaluate the chronic systemic and local toxicity of a copper intrauterine device in a rat model.
Material/Methods
Cu-IUD fragments were inserted into the uterine horns of female Wistar rats for 26 weeks (equivalent 15.42–17.33 years in humans). We tested copper at 20, 40, and 60 times the clinical dosages to study copper toxicity under severe conditions. Classic chronic systemic toxicity evaluations, including body weight, hematology, organ coefficient, and tissue reactions, were performed.
Results
The body weight of the rats increased during the 26 weeks, which showed that the Cu-IUD implant had no effect on animal growth. Histological examinations and organ coefficients of the uterus and other major organs indicated no obvious systemic or local impairment. Blood tests confirmed that the hepatic and renal functions remained normal.
Conclusions
These results obtained at different dosages and long-term implantation provide solid data confirming the safety of long-term use of Cu-IUDs. However, the elevated leucocyte levels found in this study warrant further investigation.
Objectives:
We aimed to examine the change in plasma copper (Cu) level and copper transport proteins level before inserting Cu-IUD and after one menstrual cycle and to show the effect of this change on the thiol disulfide balance in women using copper-containing intrauterine device (Cu-IUD).
Method:
Thirty-three reproductive women who admitted to the gynecology clinic and inserted Cu-IUD were examined in this study. Thiol-disulfide homeostasis, plasma Cu and ceruloplasmin levels and ceruloplasmin ferroxidase activity were measured using the blood samples collected just before inserting Cu-IUD and after one menstrual cycle.
Results:
Plasma copper level (p = 0.006), ceruloplasmin (p < 0.001), Ceruloplasmin Ferroxidase (p = 0.005), thiol disulfide homeostasis parameters; native thiol (NT) (p = 0.004), and total thiol (p = 0.003) levels increased significantly.
Conclusion:
After one menstrual cycle in women inserted intrauterine Cu-IUD for contraception, plasma levels of Cu, which is the oxidant molecule, increased significantly. Both plasma ceruloplasmin level and ceruloplasmin ferroxidase activity increased due to elevated Cu levels. This increased oxidant status in the acute period was balanced by the increase in the native thiol level.
Copper is an essential trace mineral but can be harmful in excess. Since the introduction of copper-containing intrauterine devices in the 1970s, their possible relationship to abnormal/toxic blood copper levels has been researched. Here, we summarize and interpret 12 studies that evaluate blood copper levels in users of copper-containing intrauterine devices. The data are inconclusive, with the results of eight studies indicating no increase in blood copper levels with use and the results of four studies showing significant increases in blood copper levels with use. Investigators in all studies reviewed appear to have evaluated for total copper rather than free copper (the form of copper that is toxic), which raises questions about the clinical significance of all research on this subject to date.
Abstract
Background: CuT380A intra uterine device Intra Uterine Device (IUD) is used in the health system of Iran. The most important and frequent side effects of the IUDs are hypermenorrhea and polymenorrhea. In Iran, iron supplement are not prescribed for the IUD users and there are no documents indicating their iron reservation status. This study was performed to determine the iron status in Gorganian IUD users.
Methods: This historical cohort study was performed on 100 IUD users (exposed group) and 100 non-IUD users (non-exposed group) in the Golestan province in north east of Iran in 2008. To evaluate the iron status hemoglobin and ferritin levels were measured. Data was analyzed by SPSS 13 by using Chi square and Inde-pendent T-test. A p-value less than 0.05 were considered as statistically significant.
Results: Hgb less than 10.5 was seen in 5% and 6% of IUD users and non-IUD users respectively which was not statistically significant (OR: 1.43, 95% CI: 0.39-5.25). Low Ferretin Level (less than 15) was seen in 53% of IUD users and in 35% of non-IUD users which was statistically significant (OR: 2.35, 95% CI: 1.28-4.29) Dura-tion of menstrual period in the two groups was statistically significant (7.5±2.4 vs. 6.4±1.8, p= 0.005) but inter-val of menstruation (days) was not statistically significant (26.7±4.7 vs. 28±11.2, p> 0.05).
Conclusion: On the basis of the results obtained we suggest either routine iron supplementation following ap-plication of IUD, or use of the hormone releasing IUD as an alternative for copper IUDs.
Keywords: IUD, Anemia, Iron Deficiency
Copper is an essential trace element, which is an important catalyst for heme synthesis and iron absorption. Following zinc and iron, copper is the third most abundant trace element in the body. Copper is a noble metal, like silver and gold. Useful industrial properties include high thermal and electrical conductivity, low corrosion, alloying ability, and malleability. Most of the metallic copper appears in electrical applications. Copper is a constituent of intrauterine contraceptive devices and the release of copper is necessary for their contraceptive effects. The average daily intake of copper in the US is about 1 mg Cu with the primary source being the diet. The bioavailability of copper from the diet is about 65–70% depending on a variety of factors including chemical form, interaction with other metals, and dietary components. The biological half-life of copper from the diet is 13–33 days with bilary excretion being the major route of elimination. Copper sulfate is a gastric irritant that produces erosion of the lining of the gastrointestinal tract. Chronic copper toxicity is rare and primarily affects the liver. Wilson's disease and Indian childhood cirrhosis are examples of severe chronic liver disease that results from the genetic predisposition to the hepatic accumulation of copper. The serum copper concentration ranges up to approximately 1.5 mg/L in healthy persons. Gastrointestinal symptoms occur at whole blood concentrations near 3 mg Cu/L. Chelating agents (CaNa2EDTA, BAL) are recommended in severe poisoning, but there are little pharmacokinetic data to evaluate the effectiveness of these agents.
Zn is an essential trace element for all organisms. In human subjects body growth and development is strictly dependent on Zn. The nervous, reproductive and immune systems are particularly influenced by Zn deficiency, as well as by increased levels of Zn. The relationship between Zn and the immune system is complex, since there are four different types of influence associated with Zn. (1) The dietary intake and the resorption of Zn depends on the composition of the diet and also on age and disease status. (2) Zn is a cofactor in more than 300 enzymes influencing various organ functions having a secondary effect on the immune system. (3) Direct effects of Zn on the production, maturation and function of leucocytes. (4) Zn influences the function of immunostimulants used in the experimental systems. Here we summarize all four types of influence on the immune function. Nutritional aspects of Zn, the physiology of Zn, the influence of Zn on enzymes and cellular functions, direct effects of Zn on leucocytes at the cellular and molecular level, Zn-altered function of immunostimulants and the therapeutic use of Zn will be discussed in detail.
To solve the main problems of existing coarse grained copper (CG Cu) intrauterine devices (IUD)-namely burst release and a low transfer efficiency of the cupric ions during usage-ultra-fine grained copper (UFG Cu) and single crystal copper (SC Cu) have been investigated as potential substitutes. Their corrosion properties with CG Cu as a control have been studied in simulated uterine fluid (SUF) under different conditions using electrochemical measurement methods. Long-term immersion of UFG Cu, SC Cu and CG Cu samples in SUF at 37 °C have been studied for 300 days. A lower copper ion burst release and a higher efficiency release of cupric ions were observed for UFG Cu and SC Cu compared with CG Cu in the first month of immersion and 2 months later. The respective corrosion mechanisms for UFG Cu, SC Cu and CG Cu in SUF are proposed. In vitro biocompatibility tests show a better cellular response to UFG Cu and SC Cu than CG Cu. In terms of instantaneous corrosion behavior, long-term corrosion performance and in vitro biocompatibility, the three pure copper materials follow the order: UFG Cu>SC Cu>CG Cu, which indicates that UFG Cu could be the most suitable candidate material for intrauterine devices.
Serum levels of copper and zinc were determined in 11 health women in whom Latex Leaf intrauterine devices (IUDs) containing copper and zinc had been inserted. Patients with low levels of serum copper or zinc before insertion usually had increased levels of either of these metals while using the device, but they did not exceed the upper limits of normal values. When the group was considered as a whole, the serum levels of zinc showed a slight tendency to increase with duration of IUD use, whereas there was no statistical difference between the serum levels of copper before and after insertion of the IUD.
PIP
Serum levels of copper and zinc were measured in 111 healthy women in whom Latex Leaf IUDs containing copper and zinc had been inserted. The women ranged from 21 to 41 years of age. Months of use ranged from 1 to 23 with an average of 14.6. The 1st blood sample was obtained before insertion and the 2nd from 1 to 19 months after insertion. Mean level of serum copper in the 1st sample was 1.42 mcg/ml. Age and parity had no effect; a slight tendency for higher levels was observed only in multigravidas. There were no significant changes in mean copper levels even when the levels were correlated with duration of usage. Mean serum zinc level before insertion was 1.1 mcg/ml with no correlation to age, gravidity, or parity. The 2nd sample showed a slight increase, 109% + or -3.25% standard error p .005. This increase correlated with the time the device was in situ. In general, patients with low levels of serum copper or zinc before insertion usually had increased levels after use but these levels did not exceed the upper limits of normal values. This may be due to an initially low level of the copper fraction bound to serum albumin and indicates the existence of some equilibrium between free and bound metal in the system.
Serum levels of the essential metals, iron (Fe), copper (Cu), magnesium (Mg), zinc (Zn), and calcium (Ca), were determined by atomic absorption spectrophotometry in one hundred and twenty randomly selected adult Nigerian female volunteers fitted with copper T or Delta T intrauterine contraceptive devices (IUDs) for a period of 3-18 months, and their normal age-matched controls. The mean serum concentration of all the essential metals was lower in the women fitted with copper IUDs than the control group. The differences, however, are not statistically significant (p greater than 0.05).
By means of neutron activation analysis, the concentrations of copper, zinc, manganese, sodium and potassium were estimated in the endometrium and cervical mucus in sixteen women using the Cu-T device. Copper and zinc levels in plasma were also determined as well as the protein concentration of the endometrium. Specimens were taken both in the proliferative and in the secretory phase before the insertion, during one year's use and in the first two cycles after the removal of the device. The release of copper from the devices was also assessed. The use of a Cu-T resulted in a significant increase in the protein concentration of the endometrium, which remained elevated after the removal of the device. The copper concentration of the proliferative endometrium was increased during the first three cycles, but not thereafter, whereas in the secretory endometrium, it was significantly elevated even after 11-12 cycles with the Cu-T in situ. There was a marked increase in the copper concentration of the cervical mucus during the first six treatment cycles, especially during the proliferative phase. No changes occurred in the plasma levels of copper. There was a gradual decrease in the zinc concentration of the secretory endometrium. Furthermore, there was a significant decrease in the manganese concentration of both proliferative and secretory endometrium following 11-12 cycles with the Cu-T, which did not normalize after the removal of the device. There was no consistent and systematic change in endometrial sodium; however, the potassium concentration of the proliferative endometrium was diminished. The release of copper from the devices was estimated to be 10.3 mg per year (range 7.4-13.5 mg). The data obtained indicate that - after the first two months of use - the daily release of copper from the device (approximately 45 μg) is almost constant during one year (Cu-T 200).
Zn deficiency in humans is widespread throughout the world. It is more prevalent in areas where the population subsists on cereal proteins. Conditioned Zn deficiency is seen in many disease states. Its deficiency during growth periods results in growth failure and lack of gonadal development in males. Other effects of Zn deficiency include skin changes, poor appetite, mental lethargy, delayed wound healing, neurosensory disorders, and cell-mediated immune disorders. Severe Zn deficiency, as seen in acrodermatitis enteropathica (a genetic disorder), is fatal if Zn is not administered to these patients. A clinical diagnosis of marginal Zn deficiency in humans remains problematic. Assays of Zn in granulocytes and lymphocytes provide better diagnostic criteria for marginal Zn deficiency than plasma Zn. Approximately 300 enzymes are known to require Zn for their activities. Zn is required for DNA synthesis, cell division, and protein synthesis. Recently, we learned that Zn-finger proteins are involved in genetic expression of various growth factors and steroid receptors. We suspect that several hundred Zn-containing nucleoproteins are probably involved in gene expression of various proteins. Zn deficiency adversely affects lymphocyte proliferation. This may be related to the enzymatic role of Zn in DNA synthesis and cell division. Thymulin, a thymic hormone involved in T-lymphocyte maturation, is known to be Zn dependent and is adversely affected by Zn deficiency. Thus, an adverse effect of Zn deficiency may also be in lymphocyte differentiation and maturity. Zn deficiency is known to decrease interleukin 2 production by helper T lymphocytes, and abnormalities in T-lymphocyte subpopulations have been observed in Zn-deficient humans.(ABSTRACT TRUNCATED AT 250 WORDS)
Copper is an essential trace element, which is an important catalyst for heme synthesis and iron absorption. Following zinc and iron, copper is the third most abundant trace element in the body. Copper is a noble metal, like silver and gold. Useful industrial properties include high thermal and electrical conductivity, low corrosion, alloying ability, and malleability. Most of the metallic copper appears in electrical applications. Copper is a constituent of intrauterine contraceptive devices and the release of copper is necessary for their contraceptive effects. The average daily intake of copper in the US is about 1 mg Cu with the primary source being the diet. The bioavailability of copper from the diet is about 65-70% depending on a variety of factors including chemical form, interaction with other metals, and dietary components. The biological half-life of copper from the diet is 13-33 days with bilary excretion being the major route of elimination. Copper sulfate is a gastric irritant that produces erosion of the lining of the gastrointestinal tract. Chronic copper toxicity is rare and primarily affects the liver. Wilson's disease and Indian childhood cirrhosis are examples of severe chronic liver disease that results from the genetic predisposition to the hepatic accumulation of copper. The serum copper concentration ranges up to approximately 1.5 mg/L in healthy persons. Gastrointestinal symptoms occur at whole blood concentrations near 3 mg Cu/L. Chelating agents (CaNa2EDTA, BAL) are recommended in severe poisoning, but there are little pharmacokinetic data to evaluate the effectiveness of these agents.
Zn is an essential trace element for all organisms. In human subjects body growth and development is strictly dependent on Zn. The nervous, reproductive and immune systems are particularly influenced by Zn deficiency, as well as by increased levels of Zn. The relationship between Zn and the immune system is complex, since there are four different types of influence associated with Zn. (1) The dietary intake and the resorption of Zn depends on the composition of the diet and also on age and disease status. (2) Zn is a cofactor in more than 300 enzymes influencing various organ functions having a secondary effect on the immune system. (3) Direct effects of Zn on the production, maturation and function of leucocytes. (4) Zn influences the function of immunostimulants used in the experimental systems. Here we summarize all four types of influence on the immune function. Nutritional aspects of Zn, the physiology of Zn, the influence of Zn on enzymes and cellular functions, direct effects of Zn on leucocytes at the cellular and molecular level, Zn-altered function of immunostimulants and the therapeutic use of Zn will be discussed in detail.
A 12-month followup study was undertaken to evaluate the effect of using the copper T-200 IUD on hemoglobin in trace element levels in Nigerian women. A total of 45 women were studied, including 20 who were using that IUD and 25 controls. The results indicated that after 12 months, the mean serum zinc and iron levels in the study group were significantly lower (p0.01) than initial concentrations and that of normal nonusers. This was true for both hemoglobin and hematocrit values (p0.05). However, serum copper increased significantly in the study group (p0.01). It is suggested that the low zinc status was probably responsible for the menorrhagia which was common among the study group using copper IUDs, which in turn was responsible for the anemia seen in more than 50% of the IUD users. However, the decreased in iron and zinc as well as the increase in copper levels may be a result of alterations during the acute phase response associated with the insertion of the Cu T-200. The monitoring of hemoglobin and serum iron levels as well as zinc levels may thus enhance the prophylactic use of IUDs to control menorrhagia, which leads ultimately to the development of anemia in this group. author's modified
Copper T380A is one of the most commonly prescribed intrauterine devices (IUDs). However, there are few reports of its systemic health effects. This study evaluates the association between the use of T380A IUD and blood Cu levels in a group of Mexican users.
Eighty-six T380A users and eight nonusers were recruited. Blood Cu levels were measured using an atomic absorption spectrophotometic technique.
In IUD users, mean blood Cu level was significantly higher than in nonusers, 216.63 vs. 107.47 microg/dL (p<or=.001), and above the normal blood Cu level range of 80-160 microg/dL. No significant difference in blood Cu levels was observed by age or length of time of IUD use.
The observed higher blood Cu levels among T380A user stands out in sharp contrast to previous reports of other types of Cu IUDs. Further research should evaluate if the observed levels are associated to toxic effects with the general population or special groups.
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