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Copper-bearing intrauterine devices are being increasingly used for contraception. A growing number of pregnancies, which may subsequently carry to term, are therefore being exposed to high levels of copper at the critical period of organogenesis, with risk of possible teratogenesis. Two cases of anencephaly occurring in association with these devices are reported.
A copper intrauterine device (Cu-IUD) was inserted transabdominally into the uterine cavity of eight Japanese monkeys (Macaca fuscata fuscata) for 4 to 6 months, and effects on various organ functions were examined. Results showed no significant effects on the menstrual cycle length, serum levels of LH, estradiol-17 beta, progesterone or clinical biochemical data such as serum copper, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, lactic dehydrogenase, and blood urea nitrogen. Histology revealed edema and infiltration of eosinophilic leukocytes in the endometrium treated with a Cu-IUD.
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The mechanism of copper intrauterine device (Cu IUD) in limiting intrauterine infections is poorly understood. Copper ions may enhance the release of reactive oxygen species which are deleterious to the microbes. The present study compares the oxidative responses of adherent cell population of uterus prior to Cu-T insertion and at different post-insertion intervals. Increase in reactive oxygen intermediates was evident at 1 week post-insertion. However, the release of active oxygen species decreased thereafter. Further, these responses were only a local phenomenon as the peripheral blood monocytes failed to produce appreciable change following Cu-T insertion. Results suggest the protective role of active oxygen species in Cu IUD users which lasts for a brief period. The withering of respiratory burst activity later on may possibly prevent endometrial damage.
The mechanism of copper in limiting intrauterine infections in intrauterine device (Cu IUD) users is poorly understood. Copper ions may enhance the release of reactive oxygen radicals, which in turn decrease the release of reactive nitrogen intermediates (RNI). RNI are known to have bactericidal effect. The present study compares the levels of RNI prior to Cu-T insertion and at different post-insertion intervals up to 12 weeks. The decrease in RNI was evident by one week and continued until 12 weeks. Therefore, the bactericidal effect of copper in IUD is via reactive oxygen intermediates. The superoxide anion inactivates this active intermediate nitric oxide. Therefore, excess of superoxide radical will markedly shorten the half-life of nitric oxide but will not prevent its conversion to nitrites and nitrates.
OBJECTIVE: To determine whether the insertion of a copper intrauterine device can restore regular menses in patients with functional secondary amenorrhea. DESIGN: Prospective, observational study. SETTING: Clinical practices. PATIENT(S): Forty-eight volunteers with functional secondary amenorrhea. INTERVENTION(S): Insertion of a copper intrauterine device. MAIN OUTCOME MEASURE(S): Restoration of menses. RESULT(S): In 40 patients, regular menses were restored within a few weeks after insertion of the device. Normal menses were maintained as long as the copper intrauterine device remained in place. After removal of the device, normal menses persisted for 1 year. CONCLUSION(S): Insertion of a copper intrauterine device restores regular menses in women with functional secondary amenorrhea. The mechanism of action of the device probably is related to the release of prostaglandins from the endometrium.
Sixteen cases with uterine perforation by a copper intrauterine device (IUD) are presented. In 13 cases the IUD had been inserted within 5 months following delivery, and in 6 cases the insertion had been painful. Missing string was the first sign in most cases. Laparatomy was performed in all cases to remove the IUD. The IUD was adherent to omentum or sigmoid in 10 cases. There is an increased risk of uterine perforation if the IUD is inserted postpartum during lactation and involution of the uterus. Therefore a painful IUD insertion and a missing string demand investigation of a partial or complete perforation.
The effects of copper ions on the binding of steroids to receptors revealed that the inhibitory effect of Cu++ was apparent at 10(-6)M, ANd the binding capacities decreased to 10% at 10(-2)M Cu++. The kinetic study demonstrated that Cu++ was a competitive inhibitor of steroid hormone-receptor binding (Ki divided by 2.7 X 10(-5)M to estrogen receptor; Ki divided by 5.1 X 10(-6)M to progesterone receptor). These results indicate that copper ions interfere at the steroid-binding site of receptor and that progesterone receptor is more affected by copper ions than is estrogen receptor. The sedimentation pattern showed the dissociation and aggregation of receptor macromolecules by copper. These phenomena may indicate the biologic inactivation of receptor. In fact, morphologically, progestational proliferation was severely inhibited and estrogenic action seemed to be inhibited. The Timm stain showed copper uptake by endometrial epithelium and superficial stromata. The copper content apparently increased in the cytoplasm of uteri bearing a copper intrauterine device, compared with controls. In vivo, the concentration of cytoplasmic copper was approximately 1.4 X 10(-6)M, which was obviously inhibitory to steroid hormone-receptor interaction. However, complete morphologic suppression of the progestational effect by copper cannot exclude the coexistence of some other mechanism in these phenomena.
The mechanism of action of copper in copper intrauterine devices (Cu IUD) as an antimicrobial agent is not well understood. Copper and iron are supposed to be responsible for release of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), which are very active in the presence of infection. The copper in a copper IUD could be responsible for limiting pelvic inflammatory disease. The present study was composed of 20 IUD seekers in whom ROI and RNI were studied before insertion of Cu IUD and then at 1, 4, and 12 weeks afterward. ROI showed a rise after insertion, whereas RNI showed a steady decline. Hence, it is presumed that the rise in ROI could be responsible for both the bactericidal effect of Cu IUD and also for the fall in RNI.
Often when copper intra-uterine contraceptive devices are removed they are found to have deposits on them. Studying these deposits with photonic microscopes and with scanning electronic microscopes and with fluorescence X and X diffraction shows that mostly these deposits are of calcium in the form of calcite. These crystals are not toxic but the fact that they are crystalline could give rise to microtraumatism. The study also shows that there are individual variations between patient and patient and the length of time these intra-uterine devices have been in the uterus is not an important factor in the appearance of these deposits. The phenomenon of dissolution and recrystallisation in situ of the calcite can be a trap because it can be a reservoir for micro-organisms.
To evaluate the risk of iron deficiency and anemia connected with the use of modern copper intrauterine devices, serum ferritin, transferrin, iron, hemoglobin and hematocrit levels, red cell counts, and morphology, as well as red cell indexes were determined in 40 women and in 19 controls. Follow-up was for one year. Mean hemoglobin, hematocrit, serum iron, and serum ferritin levels decreased and serum transferrin levels increased significantly in the study population. About 20% of intrauterine device users but none of the controls showed signs of iron deficiency, and 10% had clinical anemia at 12 months of use. No differences were found between the three different copper intrauterine devices tested (Nova T, Multiload and Fincoid). Because the risk of anemia did not correlate with subjective evaluation of the amount of bleeding, it is recommended that hemoglobin levels should be determined for all intrauterine device users before its insertion and at six and 12 months of use. In those with decreased hemoglobin levels, serum ferritin should be measured and iron replacement instituted or the device removed.
The antifertility effect of copper-bearing IUDs is based on continuous release of copper, which is a result of the reaction between the metal and the uterine secretions. Released cupric ions collect in the endometrium and in the uterine fluid but significant accumulation has not been found in the bloodstream or elsewhere. Following Laker's suggestion that hair be used for monitoring essential trace elements, e.g., copper, we checked the copper content of the hair of women wearing copper-bearing IUDs. Samples of untreated pubic hair removed by clipping before diagnostic curettage were obtained from 10 young (24-34 years old), white caucasian females who until then had been wearing an MLCu250 IUD for more than 1 year. Pubes from 10 comparable (sex, age, race) subjects who had never used a Cu-containing device served as controls. The unwashed material was submitted to the toxicology laboratory, where the copper content was assessed by flameless atomic absorption, a technique whose lower limit of measurement lies at a concentration of 0.05 mcg Cu/ml fluid (50 ppb). Hair samples were washed to remove extraneous traces of metal according to the prescriptions of the International Atomic Energy Agency, weighed, and mineralized, after which a small volume (10 mcl) of the diluted fluid was fed into the graphite furnace. Each sample (75-150 mg) was analyzed 4 times, both before and after washing. Since the cleaning procedure reduces the weight of the sample (mainly by the removal of fat, dust, etc.) this explains why the percentage copper content of washed hair is higher than that of unwashed hair belonging to the same subject. The results indicate that there was no significant difference (Mann-Whitney U test) between the mean copper levels of both unwashed and washed pubes from women who were using or had never used an MLCu250 IUD. We therefore conclude that the use of this copper-containing device is not associated with significant accumulation of copper in (pubic) hair.
OBJECTIVE: To assess the risk of ectopic pregnancy when using copper intrauterine devices relative to non-use of contraception and female sterilization. DESIGN: Case-control study. MATERIAL AND METHODS: All cases diagnosed with a histologically verified extrauterine pregnancy and who became spontaneously pregnant in one Norwegian county from January 1, 1987 through to December 31, 1990 were eligible. Non-pregnant control women were chosen at random from the Norwegian Population Registry. Eligible for study were sexually active women, from 20 to 39 years of age, and who defined themselves as fecund. Included in the final analyses were 168 cases and 1,169 controls, who had all been previously pregnant. STATISTICAL METHODS: Chi square test and unconditional logistic regression. RESULTS: Compared with non-users of contraception, the adjusted odds ratio (aOR) among current users of copper intrauterine devices was 0.09 (95%, confidence intervals (CI); 0.06-0.13). Compared with women who were sterilized, the aOR of having an ectopic pregnancy among current copper IUD users was 1.6 (95% CI; 0.7-3.5). CONCLUSION: Relative to non-users of contraception, current copper IUD users had a 91% (95% CI; 87-94%) protection against ectopic pregnancy, while compared with women who had had a tubal sterilization, current copper IUD users had a 60% non-significant increased risk of ectopic pregnancy.
Copper release from copper-bearing IUD's was studied in vitro and in vivo using atomic absorption spectrophotometry in deionized water, normal saline solution and normal ovulatory cervical mucus. In these media, copper release from a 375 mm2 DIU occurs without latency, showing comparable amounts for identical time intervals. Daily copper release was shown to be respectively 8 and 11 times higher in cervical mucus and normal saline solution than in deionized water. Although copper ions are detectable in ovulatory cervical mucus under physiological conditions, the copper content appears 5 to 6 times higher in women bearing a copper IUD. Obviously, the copper amount is dependent on the copper exposed surface: the daily in vitro release from a 250 mm2 IUD is 18% inferior to that observed from a 375 mm2 model. In vivo, the daily copper release in ovulatory mucus of 380 or 200 mm2 IUD users is respectively 5 and 3.5 times higher than in controls.
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This study was designed to examine the teratogenic potential of copper releasing intrauterine contraceptive devices on the developing embryo. The tissues and organs of 11 whole embryos between 7 and 12 weeks of gestation were histologically examined for copper absorption after exposure to a copper intrauterine device in utero. The findings were not significantly different when compared with a control group of 7 embryos. No malformation or copper aggregates were observed in the various organs and placentas. The observations in this small sample would suggest that the copper-releasing intrauterine device has no deleterious effects on fetal development. The question remains whether malformations reported in some cases are associated with copper deposits in the tissues or with free copper ions in the fetal circulation. The implications are discussed.
A study was undertaken to determine whether long-term use of a copper intrauterine device (IUD) was associated with any alteration in the serum copper levels and thereby whether absorption of copper from the device in utero could result in copper toxicity. Serial estimations in copper IUD wearers showed that there was no alteration in serum copper levels for a period of up to 24 months. The mean range and frequency distribution of serum copper levels in long-term copper IUD wearers was similar to that seen in the normal population. There was no difference in the mean 24-hour urinary copper excretion between the control group and the copper IUD wearers. Data suggest that the copper released from a copper IUD may not be readily absorbed from the uterine fluid. This hypothesis needs verification.
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