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Copper Release from Copper-T Intrauterine Devices
Abstract
In this investigation of the copper loss in utero from the Copper-T, the release rate was estimated by iodometric titration and the corrosion was microscopically examined in ground plastic casts. The release rate was determined in 28 preweighed Copper-Ts with a surface area of 100–400 mm2 during the first month, and in 60 Copper-T-200s (TCu-200) which had been used for 5.3 to 40.3 months. The depth of corrosion was measured in 68 TCu-200s used for 3.2 to 52.0 months.During the first month the copper release from preweighed Copper-Ts with a surface area of 100,200,300 or 400 mm2 was 26.3, 44.4, 75.2 and 73.6 μg/day, respectively. The release rate increased with increasing surface area up to 300 mm2, but not thereafter. The average release rate of the TCu-200s was 43.8 μg/day from the 21st up to the 41st months of use. However, the release rate was significantly higher in devices removed because of bleeding. In these, it was twice or even four times as high as in the devices removed from symptom-free patients. Metallurgic micrographs revealed both inter- and intraindividual variations in corrosion of the wire. Wire breakage occurred as early as in the 12th month of use, and the risk of breakage was about 30 per cent during the fourth year.Owing to the corrosion, a replacement of TCu-200 seems indicated in symptom-free patients every three years, in patients with abnormal bleeding even more often. The life time of copper IUDs could be prolonged by increasing the thickness of the wire and by supplementing it with a non-corrodable (e.g. silver) core, which would eliminate the fragmentation due to corrosion. Moreover, an increase of the wire surface to 300 mm2 would probably reduce the pregnancy rate.
... In recent decades, understanding of the problems with Cu-IUDs has improved. There are two leading hypotheses about the causes of adverse side effects: (1) the physical rigidity of Cu-IUDs that leads to irritation 22 , and (2) the presence of Cu 2+ that cause an inflammatory response in the uterine lining 23 . This understanding has laid the foundation for the research activities outlined in this section. ...
... A drop in side effects was reported for the flexible VeraCept Cu-IUD, likely due to its smaller Cu surface area, generating a smaller quantity of Cu 2+ ions present 24 , which resulted in reduced inflammatory reaction within the uterine cavity. Inhibiting the "Burst Effect" of Cu-based IUDs Another proposed cause for the side effects of Cu-IUDs is the high concentrations of Cu 2+ that cause an inflammatory response in the uterine lining 23 . When first inserted, the Cu-IUD corrodes at a faster rate due to the equilibration with the uterine environment 27 . ...
... This "burst effect" of cupric ions can result in dissolution rates up to 296 μg/day and has been suggested to be responsible for excessive bleeding and pain within the first two months of use 28 . As the metal-solution interface reaches a steady state, the Cu 2+ concentration decreases over the device's life span, with an average dissolution rate of 43.8 μg/day for 21-41 months of use 23 . ...
With over 200 million users worldwide, copper intrauterine devices (Cu-IUDs) are the world’s most popular, non-hormonal, long-acting, and reversible contraception method. Cu-IUDs cause uncomfortable side effects such as longer and heavier menstruation and cramping, all of which persist for the duration of use and often lead to early removal. With the rise in concern about potential physical and psychological side effects from hormonal contraceptive use, an improvement in non-hormonal contraceptive options is needed to alleviate discomforting side effects and inhibit costs. This perspective article provides an overview of the current state of non-hormonal IUDs and experimental factors to consider when developing new materials that have potential as alternative contraceptives, including copper alloys, zinc, iron, and passive metals. It also explores the sustainability and socioeconomic impact of advancing non-hormonal contraceptive options and considers international policy, cultural factors, and costs that must be considered when developing these options. Overall, the article highlights the interdisciplinary nature of this field, the complexities involved in creating effective non-hormonal contraceptives, and the need for innovation and equity in contraceptive care.
... 7) Copper release from IUDs in vivo has been reported in a few studies since the technology was first developed, with an estimated release rate in the range of 0.02-0.0736 mg/day (Hagenfeldt, 1972;Timonen, 1976;Chantler et al., 1977;Thiery and Kosonen, 1987). It correlated with the surface area of the IUD and decreased with time after IUD insertion, up to 50 months (Timonen, 1976;Chantler et al., 1977). ...
... mg/day (Hagenfeldt, 1972;Timonen, 1976;Chantler et al., 1977;Thiery and Kosonen, 1987). It correlated with the surface area of the IUD and decreased with time after IUD insertion, up to 50 months (Timonen, 1976;Chantler et al., 1977). In these studies, copper was detected in the local tissues (e.g. ...
... In these studies, copper was detected in the local tissues (e.g. endometrium, cervical mucus), but there was no increase in serum copper levels from IUD use (Hagenfeldt, 1972;Timonen, 1976;Chantler et al., 1977;Anteby et al., 1978;Prema et al., 1980;Arowojolu et al., 1989). In one study, serum copper concentration increased only in women with low starting copper serum levels (Anteby et al., 1978), and in another study, serum copper was reported to be higher in 86 IUD users (0.21663 mg/dL) compared with eight non-users (0.10747 mg/dL) (De la Cruz et al., 2005). ...
Copper is an essential micronutrient and also a regulated product used in organic and in conventional farming pest management. Both deficiency and excessive exposure to copper can have adverse health effects. In this Scientific Opinion, the EFSA 2021 harmonised approach for establishing health-based guidance values (HBGVs) for substances that are regulated products and also nutrients was used to resolve the divergent existing HBGVs for copper. The tightly regulated homeostasis prevents toxicity manifestation in the short term, but the development of chronic copper toxicity is dependent on copper homeostasis and its tissue retention. Evidence from Wilson disease suggests that hepatic retention is indicative of potential future and possibly sudden onset of copper toxicity under conditions of continuous intake. Hence, emphasis was placed on copper retention as an early marker of potential adverse effects. The relationships between (a) chronic copper exposure and its retention in the body, particularly the liver, and (b) hepatic copper concentrations and evidence of toxicity were examined. The Scientific Committee (SC) concludes that no retention of copper is expected to occur with intake of 5 mg/day and established an Acceptable Daily Intake (ADI) of 0.07 mg/kg bw. A refined dietary exposure assessment was performed, assessing contribution from dietary and non-dietary sources. Background copper levels are a significant source of copper. The contribution of copper from its use as plant protection product (PPP), food and feed additives or fertilisers is negligible. The use of copper in fertilisers or PPPs contributes to copper accumulation in soil. Infant formula and follow-on formula are important contributors to dietary exposure of copper in infants and toddlers. Contribution from non-oral sources is negligible. Dietary exposure to total copper does not exceed the HBGV in adolescents, adults, elderly and the very elderly. Neither hepatic copper retention nor adverse effects are expected to occur from the estimated copper exposure in children due to higher nutrient requirements related to growth.
... A major drawback of copper IUDs is the high incidence of increased bleeding and pain following insertion. This may be related to a high initial release of copper [2][3][4]. It is also reported that 67% of women using CuT380 complained about menstrual side effects within the first year of use [5]. ...
... It is also reported that the high corrosion rates of the TCu380A IUD and TCu220C IUD in simulated uterine solution (SUS) were obtained after the first and the third days of immersion in the solution, respectively [9]. According to literature, burst release could contribute to abnormal bleeding [2,10,11]. Arancibia et al. [12] demonstrated that a burst release of copper ions occurs in the first few months after insertion, and then the release rate decreases and stabilizes gradually. Hubacher et al. [13] suggested that side effects like bleeding and pain decrease over time, which might mean that the burst release of copper is one of the causal factors. ...
Background:
The adverse effects of copper intra uterine devices such as abnormal bleeding, pain and cramps may be due in part to the burst release of copper ions during the first few months of usage. This study focuses on controlling the initial burst release of copper ions.
Study design:
This study evaluated in vitro release rates of copper for a period of one year from standard CuT380 intra uterine devices (IUD) (n=6)and from CuT380 IUDs coated with poly(DL-lactide-co-glycolide) (PLGA) films (n=6). This study characterized the coated device for its morphological changes during degradation of film by scanning electron microscopy (SEM).
Results:
CuT380 IUDs coated with PLGA film with a thickness of 0.10±0.02mm showed a reduced initial copper release (40-80μg/day) compared with uncoated CuT380 IUDs (150-200 μg/day). Statistically significant (P<0.05) results were obtained at different time intervals during the overall study period of one year. SEM images showed degradation of coating.
Conclusion:
Coating a CuT380 IUD with biodegradable polymer reduced the initial copper release without affecting release at one year. Clinical trials are required to determine whether this could reduce side effects such as bleeding and pain associated with copper containing intra uterine devices.
... 4 Large-scale epidemiologic studies indicate that adverse effects, such as spotting, pain, and intermenstrual bleeding, are still the main obstacles frequently associated with discontinuation of the Cu-IUDs. [5][6][7] All those adverse effects are most likely relevant to the burst release of copper ions in the first few months of usage. It has been demonstrated that a burst release of copper ions occurs in the first few months after insertion, and then the release rate RETRACTED ARTICLE: Alterations in the endometrium of rats, rabbits, and Macaca mulatta that received an implantation of copper/low-density polyethylene nanocomposite decreases and stabilizes gradually. ...
... The entire genital tract is reported to be exposed to 25-80 µg/day of cupric ions released from an inserted Cu-IUD. 6,8,51 That is to say, the cupric ion concentration released by the existing Cu-IUD in uterine fluid is apparently much larger than the minimal cupric ion concentration needed to ensure contraceptive efficacy. ...
Hu L, Wang H, Rao M, et al. Int J Nanomedicine. 2014;9(1):1127–1138.
We, the Editors and Publisher of International Journal of Nanomedicine, have retracted the following article.
Following publication, the authors raised concerns about the duplication of images within the article. Specifically, The images for Figure 4C and 4F have been duplicated, as have the images for Figure 4D and 4E.
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It was noted that some images for Figures 2 and 10 may have duplicated regions, however, this was caused by an error during the publication process.
When approached for an explanation, the authors were cooperative but wereg unable to provide an adequate explanation for the duplicated images and not all the original data for the study was available. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors agreed with this decision.
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... Traditionally, influx of inflammatory cells resulting from copper concentrations in the endometrial tissue has been postulated to create a hostile environment for the embryo, thus contributing to the IUD mode of action. (4-7) Timonen and Kosonen investigated copper release from copper-T IUDs and the corrosive lifespan of copper in utero respectively; they observed sustained low pregnancy rates even when the device was approaching the end of the copper releasing lifespan, raising the question as to whether the mode of action can be explained by the release of copper alone (8,9). ...
... Copper containing IUDs are the most widely used reversible contraceptive worldwide (1)(2)(3). Copper-T IUD's demonstrate a persistently low failure rate, even at the end of the corrosive lifespan of copper in utero; thus suggesting that the mode of action cannot be explained by copper alone (8,9). Alterations in endometrial morphology and biochemical composition disrupt processes required for endometrial receptivity and implantation (34). ...
To characterize human endometrial HOXA10 expression in patients using a copper intrauterine device (IUD).
Case-control study.
Academic medical center.
Women using copper IUDs.
Immunohistochemical analysis of endometrial HOXA10 expression in biopsy samples obtained from 24 women using a copper Paraguard T380A as well as in samples obtained from 10 normal cycling women who were not using an IUD or hormonal contraceptives.
Endometrial HOXA10 expression.
Endometrial HOXA10 expression was markedly decreased in the biopsy samples obtained from women using the IUD contraceptive when compared with controls. The mean H score for endometrial stromal cell HOXA10 expression in samples obtained from women using the Paraguard IUD was 0.21 compared with 2.2 in the control endometrial biopsy samples. Endometrial glandular expression of HOXA10 was absent in all IUD users.
Decreased endometrial HOXA10 expression was apparent in women who use a copper IUD. Expression of HOXA10 is essential for endometrial receptivity. A novel mechanism of copper IUD action involves suppression of genes required for endometrial receptivity. The dramatic decrease of endometrial HOXA10 in response to IUD use may contribute to contraceptive efficacy.
... The procedure for testing the fertility of the rats was exactly as described by Ahsan Restoration offertility after removal of the device The rats had all been infertile during the time the copper wire was inserted. As shown inTable 5, many of the males were fertile again by 90 days after removal of the device.Jain, 1975; Timonen, 1976). ...
... The release rates obtained in vivo suggest that the intravas device would be effective for about 1 year, but breakage of the wire occurred during the 3rd and 4th month of use. Similarly, on the basis of release rate the life-span of Tcu-200 has been estimated to be slightly over 7 years (Timonen, 1976), but the life of the devices in practical terms is related to the corrosion and breakage. Improved life-spans of IUDs have been obtained by using another substance for the core (Sikov, Divine & Hackett, 1976). ...
A 1.5 cm long copper wire caused complete inhibition of fertility in male rats when placed properly in the vasal lumen. The contraceptive effectiveness of the device was directly proportional to the surface area of the device and was non-obstructive. The release rate of copper in vivo from a 1.5 cm long wire was 11.6 micrograms/day during the first month and 6.8 micrograms/day over the first 3 months. The contraceptive action of the wire starts about 20 days after insertion. Fertility was regained in 67% of the rats by 90 days after removal of the device. Similar devices of stainless steel and silver did not affect fertility.
... leaching is in the form of complexes, avoiding the toxicity of copper in its free form (Timonen, 1976 An iUPOD is an intrauterine device made of 3 magnetic units (Fig. 1) . CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. ...
This preliminary study evaluated the effectiveness of a novel hormone- and drug-free copper intrauterine device POD (CuiUPOD) with one to three copper-coated magnetic units in controlling Streptococcus equi subsp. zooepidemicus in seven intrauterine-inoculated mares. Initially, one unit was inserted into each mare and animals were followed weekly with trans-rectal ultrasonography, blood progesterone assay, uterine swabs for cytology and microbial culture, uterine specimens for biopsy, and trans-abdominal detection of the CuiUPOD using a handheld magnetic detector or a cell phone compass. Infection persisted after a CuiUPOD with one magnetic unit was inserted, but subsided shortly after two additional magnetic units were added. By day 60, at device removal, and after a 30-day exposure to copper, none of the mares presented with clinical signs of infection. On a scale of I-III (I, IIA, IIB, III), with I representing a healthy uterus, endometrial biopsies at the time of CuiUPOD removal, showed improved biopsy scores in two of seven mares (29%; p < 0.05). The in vivo experiments, complemented by an in vitro experiment, demonstrated a time- (24-96 hours) and dose-dependent response to Cu: three CuiUPODs - OD readings = 0.538; two CuiUPODs - OD = 0.513; and one CuiUPOD - OD = 0.452. As the concentration of copper increased, so did the antimicrobial effect. These findings suggest a promising use for the one-time application of a CuiUPOD with two or three magnetic units to mitigate uterine infections in mares.
... The total dose of copper used in the present study ranged from 2.4 to 9.6 mg, with little to no copper gel remaining visible on ultrasound assessment 5À10 min after application. In contrast, the copper intrauterine contraceptive device typically releases around 40À60 mg of copper per day, every day, with the rate of release potentially exceeding 100 mg per day immediately after insertion (Timonen 1976;Larsson et al., 1981). This high daily and cumulative dose of copper results in adverse changes to the endometrium, such as breakdown of the epithelial, stromal thrombosis and leukocyte infiltration (Sheppard, 1977). ...
... Copper is a noble metal that is often used as a corrosionresistant material for high-performance applications such as nuclear waste containers, [243,244] antimicrobial surfaces, [245,246] and intrauterine devices. [247,248] However, passivity is a prerequisite for Cu's performance under highly corrosive environments to ensure a slow corrosion rate. At high pH, Cu is susceptible to localized corrosion (i.e., pitting and crevice corrosion). ...
Passive films are essential for the longevity of metals and alloys in corrosive environments. A great deal of research has been devoted to understanding and characterizing passive films, including their chemical composition, uniformity, thickness, porosity, and conductivity. Many characterization techniques are conducted under vacuum, which do not portray the true in‐service environments passive films will endure. Scanning electrochemical probe microscopy (SEPM) techniques have emerged as necessary tools to complement research on characterizing passive films to enable the in situ extraction of passive film parameters and monitoring of local breakdown events of compromised films. Herein, we review the current research efforts using scanning electrochemical microscopy, scanning electrochemical cell microscopy (or droplet cell measurements), and local electrochemical impedance spectroscopy techniques to advance the knowledge of local properties of passivated metals. The future use of SEPM for quantitative extraction of local film characteristics within in‐service environments (i.e., with varying pH, solution composition, and applied potential) is promising, which can be correlated to nanostructural and microstructural features of the passive film and underlying metal using complementary microscopy and spectroscopy methods. The outlook on this topic is highlighted, including exciting avenues and challenges of these methods in characterizing advanced alloy systems and protective surface films.
... Copper release kinetics show an average of 40 µg/day exposure to mucosal epithelia in the uterus for up to 3 years or more. [63] It is interesting in this perspective that copper-based intrauterine devices are not associated with incidences of fibrosis or any report of collagen/extracellular matrix disorder. These contradictory factoids raise doubt about the involvement of copper in the OSMF disease process. ...
... The number of Cu-IUD indicates the copper surface area, for instance, 380 mm 2 for a TCu380A and 300 mm 2 for a CuT300. A direct relationship has been reported between the size of a Cu-IUD (higher contact surface with the endometrium) and the quantity of synthesized prostaglandin E 2 (PGE 2 ) (Timonen, 1976;Roldán Rodríguez-Marín et al., 1993). According to the ASTM B170-99 (2015) standard and the unified numbering system (UNS), the copper wire is referred to as grade 1 (also designed as C10100) of about 0.40 ± 0.01 mm in diameter, has a purity of at least 99.99%, and is the highest purity oxygen-free electronic copper with a maximum limit of 0.0005%. ...
A systematic review of the literature about the corrosion of copper in intrauterine devices (IUDs) was conducted, an important topic of copper application that apparently may not be well known to a broad corrosion audience. Copper IUDs (Cu-IUDs) are one of the most widely used contraceptive methods around the world, particularly in China, India, and Latin America. The contraceptive method is based on the release of copper ions from a Cu-IUD. Copper ions enhance the inflammatory response in the uterine cavity and reach concentrations in the luminal fluids of the genital tract, which are toxic for spermatozoa and embryos. A description is made of the different types of Cu-IUD used, the traditional T-shaped device, copper nanoparticles inside a polymeric matrix, and other shapes. This review aims to discuss the main parameters affecting the efficiency of a Cu-IUD, the contraceptive mechanism, and the shape of the device. The high copper corrosion rate immediately after insertion in the uterus (“burst release”) is discussed, which presents values of the order of up to 296 μg/day, causing side effects such as bleeding and pain, with an exponential decay defining a steady-state plateau after 1–2 months of insertion with values of 40 μg/day for a 200 mm ² Cu-IUD. This plateau is maintained over the life span of a Cu-IUD, in which the copper dissolution rate is as low as 2 μg/day for a Cu-IUD with indomethacin keeping up the contraceptive action mechanism, the concentration of copper that needs to be higher than 10 ⁻⁶ mol/l.
... Although it is not exactly known how much copper is necessary for contraception, studies suggest that a good contraceptive efficacy is obtained with IUDs having a minimal surface area of 200 mm 2 . Moreover, when the surface area exceeds 380 mm 2 , no additional reduction in failure rate is perceived, a phenomenon that can be attributed to the limited amount of dissolving agent present necessary for in utero copper dissolution [7,8]. ...
... It is known that the contraceptive effect depends mainly on the copper ions released as consequence of copper corrosion in uterus (Holland and White, 1988;Ortiz et al., 1996;Roblero et al., 1996). Because corrosion limits the efficiency and time of use of the device, some studies have focused on the rate of copper release in vivo and in vitro (Bastidas and Simancas, 1997;Kjaer et al., 1993;Kosonen and Thiery, 1983;Thiery and Kosonen, 1987;Timonen, 1976). Generally, two events of the copper degradation (mainly wire fragmentation) in uterus are accepted: first the accelerated release of copper by the influence of pH and deposition of corrosion products (Bastidas et al., , 2001Mora et al., 2000;Yuan et al., 1986), and secondly the deposition of proteins, anti-inflammatory agents, blood, cell debris and calcification (Rizk et al., 1990;Valdez et al., 2000;Xue et al., 1998;Zhu et al., 1999). ...
A corrosion study of the intra-uterine device, “TCu 380?A”, was made using cyclic voltammetry (CV), scanning electron microscopy (SEM) and optical microscopy (OM). Blood plasma, whole blood and artificial uterine fluid were used as corrosive media in order to establish a comparative scheme of the corrosion behaviour of copper in the device. In summary, the results obtained were not only similar to work reported previously, but also provided complementary data for a better understanding of the corrosion problem.
... Most of today's contraceptive intrauterine devices (IUDs) contain metallic copper in a form of sheet or wire. Rapid release of cupric ions in the first few days after implantation of IUD can cause adverse effects such as pelvic inflammatory disease, bleeding and expulsion (Timonen 1976; Farley et al. 1992; Mora et al. 2002 ). Low density polyethylene-copper nanoparticles composites show sustained, zero-order kinetic of copper ions release, therefore can be used to replace conventional IUDs (Cai et al. 2005). ...
Copper is one of the most interesting elements for various biomedical applications. Copper compounds show vast array of biological actions, including anti-inflammatory, anti-proliferative, biocidal and other. It also offers a selection of radioisotopes, suitable for nuclear imaging and radiotherapy. Quick progress in nanotechnology opened new possibilities for design of copper based drugs and medical materials. To date, copper has not found many uses in medicine, but number of ongoing research, as well as preclinical and clinical studies, will most likely lead to many novel applications of copper in the near future.
... However, tests in vitro failed to show any significant difference in toxicity between cuprous and cupric ions (Table 2). Hagenfeldt (1972) and Timonen (1976), using different techniques, agree that, after an initial high loss rate, approximately 45 µg copper/day is lost from an IUD in women. Assuming a uterine fluid volume in women of 1 ml, a copper concentration of 710µ would be reached. ...
Concentrations of cuprous and cupric chloride of 50 micrometer or greater completely inhibited the development of mouse morulae and early blastocysts into blastocysts in vitro. The zona pellucida was completely dissolved at concentrations of 250 micrometer cupric and 500 micrometer cuprous ions. No significant difference in toxicity was found between the cuprous and cupric ion at 0-50 micrometer. The addition of protein, as BSA, to the culture medium partly protected the embryos against the toxic effect of both copper ions. At a concentration of 25 micrometer a significantly higher level of BSA was required to protect against the cupric than the cuprous ion. Increasing the concentration of either ion increased the level of BSA required to exert a protective effect.
The existing adverse effects of copper in copper-containing intrauterine devices (Cu-IUDs) have raised concerns regarding their use. These adverse effects include burst release of cupric ions (Cu²⁺) at the initial stage and an increasingly rough surface of the Cu-IUDs. In this study, we investigated the use of two copper alloys, Cu-38Zn and H62 as the new upgrading or alternative material for IUDs. Their corrosive properties were studied in simulated uterine fluid (SUF) by using electrochemical methods, with pure Cu as a control. We studied the in vitro long-term corrosion behaviors in SUF, cytotoxicity to uterine cells (human endometrial epithelial cells and human endometrial stromal cells), in vivo biocompatibility and contraceptive efficacy of pure Cu, H62, and Cu-38Zn. In the first month, the burst release rate of Cu²⁺ in the Cu-38Zn group was significantly lower than those in the pure Cu and H62 groups. The in vitro cytocompatibility Cu-38Zn was better than that of pure Cu and H62. Moreover, Cu-38Zn showed improved tissue biocompatibility in vivo experiments. Therefore, the contraceptive efficacy of the Cu-38Zn is still maintained as high as the pure Cu while the adverse effects are significantly eased, suggesting that Cu-38Zn can be a suitable potential candidate material for IUDs.
Statement of Significance
The existing adverse effects associated with the intrinsic properties of copper materials for copper-containing intrauterine devices (Cu-IUD) are of concern in their employment. Such as, burst release of cupric ions (Cu²⁺) at the initial stage and an increasingly rough surface of the Cu-IUD. In this work, Cu alloyed with a high amount of bioactive Zn was used for a Cu-IUD. The Cu-38Zn alloy exhibited reduced burst release of Cu²⁺ within the first month compared with the pure Cu and H62. Furthermore, the Cu-38Zn alloy displayed significantly improved biocompatibility and a much smoother surface. Therefore, high antifertility efficacy of the Cu-38Zn alloy was well maintained, while the adverse effects are significantly eased, suggesting that the Cu-38Zn alloy is promising for a Cu-IUD.
A randomized study was performed for the comparison of two copper-releasing intrauterine contraceptive devices (IUDs), the Nova-T and the Copper-T-200, simultaneously in Denmark, Finland, and Sweden. Five years' experience demonstrated that Nova-T users had a significantly lower pregnancy rate than Copper-T-200 users. The Pearl index over 5 years was 0.8 for Nova-T users and 2.0 for Copper-T users. The performance and tolerance of the Nova-T were less affected by parity and age than was the performance of the Copper-T. Infections were treated by removal of the device and with antibiotics. The cumulative rate of removals because of infections and suspected infections was below 5 with both devices over 5 years. The copper wire in the Nova-T has a silver core which prevents corrosion-induced fragmentation of the wire. Hence, the effective lifetime of this device is more than 5 years. The results indicate that the Nova-T, which is easy to insert and remove and is associated with a low pregnancy rate and a low medical termination rate, is a real improvement over other IUDs.
The influence of corrosion on the copper wire in the Copper T-200 intrauterine device (IUD) was studied in devices which had been in utero for 3 to 52 months. This was done mainly by examining cross-sections of the wires under a light microscope. Corrosion was normally localized to narrow areas and led to breakage and fragmentation of the copper wire. Neither deposits on the wire nor corrosion products prevented the dissolution of the copper. The progress of the corrosion over a given time was determined by comparing the depth of corrosion with the original dimension of the wire. The lifetime of the IUD was evaluated on the basis of the progress of corrosion, the calculated copper release, and the number of cases of wire breakage. It was found that the Copper T-200 could be left in place for up to 45 months.
A study has been performed covering the clinical consequences of copper intrauterine device insertion in 103 insulin-dependent women and in 119 nondiabetic control subjects. Furthermore, the progress of corrosion has been measured in 15 intrauterine devices removed from diabetic women, and the results were compared with data obtained from nondiabetic women. The clinical data did not reveal any differences in the total continuation rates or in the removal rates because of accidental pregnancy or pelvic inflammation between the diabetic and the nondiabetic women after 3 and 12months. Also, the maximal depth of corrosion as well as the distribution and the biochemical constitution of the corrosion products deposited on the copper wires were found identical in the two groups studied.
Copper, as a trace element, has its role in the regulation of fertility. All human tissues contain copper, which is an essential component of certain enzymes and proteins. Gräfenberg was the first to introduce into the uterus a ring, partially made of copper, for regulation of fertility in the woman (see Figure 1). In this area, however, little was known about the ‘inert’ and ‘active’ intrauterine contraceptive devices (IUDs). After a long hiatus, plastic IUDs were developed, but their shapes and overall dimensions did not conform to the uterine cavity.
To decrease the side effects associated with copper-bearing intrauterine device (Cu-IUD) such as irregular bleeding, pain and pelvic inflammatory disease, copper/zinc oxide/low-density polyethylene (Cu/ZnO/LDPE) nanocomposites were prepared for the novel material used for IUD. The profile of Cu2+ and Zn2+ release was investigated by absorbance measurements. Cu2+ release rate is inhibited in the initial stage but is not affected greatly in the later stage by increasing the mass fraction of zinc oxide nanoparticles. The similar result is obtained for Zn2+ release with the increase of copper nanoparticles, which can be explained that copper and zinc oxide nanoparticles can suppressed the dissolution each other, but provide the pathways for ions release mutually at the same time. The surface characteristic of the nanocomposite is examined by using SEM, EDX and XRD. The unwanted deposits observed on the nanocomposite are consisted of CuO, Cu2(OH)3Cl, CaNa(H2PO4)3, CaZn(H2PO4)3 and Zn4CO3(OH)6·H2O.
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.
The results of a study on the corrosion of metallic copper used in the fabrication of contraceptive intrauterine devices (IUDs) are shown. The corrosion behaviour of IUD TCu 380 A and Nova T was evaluated in uterine synthetic solution in order to simulate the uterus conditions. The corrosion processes were evaluated by polarisation, electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) electrochemical techniques. In addition, surface analyses were performed by scanning electron microscopy (SEM), and the chemical composition of the corrosion products was determined by energy dispersive X-ray (EDX). Copper exposed to the synthetic solution showed an active corrosion process during the test due to the presence of chloride ions. The formation of a spongy gel corrosion product. on the copper surface was observed in simulated solution and characterized, comparing the different results obtained in the electrochemical tests and surface analysis. The objective of this study is to generate knowledge on the IUD's electrochemical corrosion mechanisms and parameters in order to assure its successful function as a contraceptive.
There are multiple advantages to “extended use” of the intrauterine device (IUD) use beyond the manufacturer-approved time period, including prolongation of contraceptive and non-contraceptive benefits. We performed a literature review of studies that have reported pregnancy outcomes associated with extended use of IUDs, including copper IUDs and the levonorgestrel intrauterine system (LNG-IUS). Among parous women who are at least 25 years old at the time of IUD insertion, there is good evidence to support extended use of the following devices: the TCu380A and the TCu220 for 12 years, the Multiload Cu-375 for 10 years, the frameless GyneFix® (330 mm2) for 9 years, the levonorgestrel intrauterine system 52 mg (Mirena®) for 7 years and the Multiload Cu-250 for 4 years. Women who are at least 35 years old at the time of insertion of a TCu380A IUD can continue use until menopause with a negligible risk of pregnancy. We found no data to support use of the LNG-IUS 13.5 mg (Skyla®) beyond 3 years. When counseling about extended IUD use, clinicians should consider patient characteristics and preferences, as well as country- and community-specific factors. Future research is necessary to determine the risk of pregnancy associated with extended use of the copper IUD and the LNG-IUS among nulliparous women and women less than 25 years old at the time of IUD insertion. More data are needed on the potential effect of overweight and obesity on the long-term efficacy of the LNG-IUS.
Objective. – The present investigation was carried out in order to study the process of metallic corrosion of copper IUD's in utero, to precise its dynamics and location along the IUD and to appraise the influence of eventual calcareous deposition.Material and methods. – A total of 461 copper IUDs representing four standard models were screened by means of optical microscopy. Especially typical samples were studied at higher magnifications under the scanning electron microscope. The obtained data were considered in terms of statistics.Results. – It was possible to demonstrate a preferential corrosive activity in the lower part of the IUD without significant variations between the models. It was also possible to precise the steps of the process, to describe its most characteristic aspects and to study the eventual effect of severe calcareous deposition on corroded copper.Discussion and conclusions. – Intrauterine copper corrosion is a normal process which occurs preferentially in the cervical portion of an IUD and can lead to the total metal loss. Both its initiation and evolution are submitted to strong individual variations. Thick and compact vaterite deposits may thwart copper erosion in case of drastic and rapid deposition.
An increased risk of developing genital actinomy-cosis has been found with long-term use of IUDs. In this study a group of women who had used their IUDs for 60 ± 6 months was compared with a group having worn their IUDs for 36 ± 6 months. None of the women examined had symptoms of genital infection. No significant differences could be found in colonization frequency of A. israelii on the IUDs or in humoral antibody response to the bacterium.
Two metal/insulator composites, copper/low-density polyethylene (LDPE) microcomposites and copper/LDPE nanocomposites, were prepared in a uniform metal mass fraction. The corrosion characteristics of the two composites in the simulated uterine solution have been studied by cyclic voltammetry, potentiodynamic polarization measurement and electrochemical impedance spectroscopy. Results obtained during this study show that there are obvious differences on the corrosive rates and mechanisms between the two materials. The nanocomposites have stable corrosive reaction, hardly passivation, low corrosion rate and high transformation ratio of copper to soluble cupric ions compared with microcomposites, which indicate that the nanocomposites are perfect to be the novel material for intrauterine device. The corrosion behaviour of the microcomposites was controlled by both the processes of the pervasion of Cu2+ and the transfer of the charge, while that of the nanocomposites was only controlled by the transfer of the charge. This paper also compared the corrosion behaviours of the composites and bulk copper in the simulated uterine solution, there were more insoluble subproducts in the corrosion process of bulk copper than the composites. Further, the electrochemical method in this study is proved to be useful to characterize the corrosion behaviour of high electrical resistivity materials.
Measurements were made of the copper remaining on used Gravigard intrauterine contraceptive devices (IUCDs) that had been in utero for up to 40 months. The topography and composition of the surface deposits were analysed by scanning electron microscopy and energy-dispersive X-ray analysis. The rate of copper loss decreased exponentially from 0.42 mumol d-1 (26.7 micrograms d-1) upon insertion to 0.056 mumol d-1 (3.6 micrograms d-1) after 26 months of use; between 27 and 40 months of use a linear release of 0.32 mumol d-1 (20.3 micrograms d-1) was observed. There was no correlation between this changing rate of copper loss and the pregnancy rate with the device in situ. The changes in the rate of copper loss were probably due to the growth of a surface corrosion product which, due to internal stresses, fractured after about 2 years and exposed fresh copper; this results in a progressive increase in breakage of the copper wire after 3 years. It is recommended that a copper IUCD of this type be replaced after 3 years.
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Measurements were made of the copper remaining on used Gravigard IUDs that had been in utero for up to 40 months. The topography and composition of the surface deposits were analyzed by scanning electron microscopy and energy-dispersive x-ray analysis. The rate of copper loss decreased exponentially from 0.42 mcmol d-1 (26.7 mcg d-1) upon insertion to 0.056 mcmol d-1 (3.6 mcg dz-1) after 26 months of use; between 27-40 months of use, a linear release of 0.32 mcmol d-1 (20.3 mcg dz-1) was observed. There was no correlation between this changing rate of copper loss and the pregnancy rate with the device in situ. The changes in the rate of copper loss were probably due to the growth of a surface corrosion product which, due to internal stresses, fractured after about 2 years and exposed fresh copper; this results in a progressive increase in copper wire breakage after 3 years. It is recommended that a copper IUD of this type be replaced after 3 years.
The copper/low-density polyethylene (Cu/LDPE) composites has been developed as a novel intrauterine devices (IUDs) material in our research since the copper-containing IUDs (Cu-IUDs) made of this kind of material can eliminate or lessen the side-effects of the existing Cu-IUDs. In the present study tensile tests were used to characterize the mechanical properties of this novel IUDs material, the Cu/LDPE composites. The influences of the copper particles’ loading, varied from 5 to 25 wt.%, and the copper particles’ size, 50 nm and 5 μm, on the Young's modulus, yield strength, tensile strength and elongation at break were investigated. Increasing the copper particles’ loading caused an increase in Young's modulus for Cu/LDPE nanocomposite but a decrease in Young's modulus for Cu/LDPE microcomposite, a decrease in yield strength for both Cu/LDPE nanocomposite and Cu/LDPE microcomposite except for an increase in yield strength for Cu/LDPE nanocomposite when the copper nanoparticles’ loading is less than 5 wt.%, a decrease in tensile strength and elongation at break for both Cu/LDPE nanocomposite and Cu/LDPE microcomposite. Decreasing the copper particles’ size caused an increase in the Young's modulus, yield strength, tensile strength and elongation at break. These changes are attributed to the different dispersion of the copper particles in matrix and the different interfacial adhesion between the copper particles and the matrix caused by the different loadings and sizes of copper particles. Additionally, after the copper particles inside the Cu/LDPE nanocomposite was corroded completely, its mechanical properties are better than those of the original Cu/LDPE nanocomposite due to the releasing of stress concentration caused by the copper nanoparticles. All these results indicate that the Cu/LDPE nanocomposite is much better to act as a Cu-IUDs material than the Cu/LDPE microcomposite does.
Copper/low density polyethylene (LDPE) composites covered with LDPE film on the surface were prepared for intrauterine contraceptive device (IUD). Cu2+ release rates of the composites were determined by absorbance measurements. The surface characteristics of the composites after incubated for 5 months were investigated by SEM and EDX techniques. The results show that the existence of LDPE film on the surface of the composites decreases the release rate of Cu2+, especially the burst release of Cu2+ at initial period. The undesirable deposits, which are observed on the surface of the composite without LDPE film, are not detected on the surface of the composite with LDPE film, indicating that the presence of LDPE film can effectively prevent the formation of deposits on the composite surface. Results obtained from this study suggest that the existence of LDPE film on the composite surface may alleviate the side effects (bleeding, abdominal pain and inflammatory complication) of IUD resulting from the burst release and the deposit formation.
ObjectiveTo compare the cupric ion releasing in vitro of the three IUDs.MethodsThe stability of cupric ion releasing of IUDs including TCu 380A IUD (TCu 380A), Multiload Cu375 IUD (MCu 375) and Yuangong 365 copper-bearing indomethacin-releasing IUD (Yuangong 365) by the determination of cupric ion releasing in simulated uterine fluid. The simulated uterine fluid was used for releasing media. Copper ion was determined by flame atomic absorption spectrometer.ResultsThe cupric ion releasing of three IUDs were instable at the beginning and tend to be stable gradually. In the stable phase, the average level of cupric ion releasing of TCu380A, MCu375 and Yuangong 365 were 4.25±2.71-7.62±6.42 μg, 4.92±1.23-8.62±3.08 μg and 2.19±0.40-4.68±1.66 μg, respectively. TCu380A had higher instable releasing level than those of Yuangong 365 (P<0.05).ConclusionTCu 380A and MCu 375 showed a “burst release” during the first few days and the former was of great significance(P<0.05). The initial cupric ion releasing of Yuangong 365 appeared to be the lowest, followed by MCu375 and TCu380A in a releasing order.
To avoid the inherent disadvantages of copper-containing intrauterine device (Cu-IUD) induced by free Cu²⁺, two other well-performing metal ions, namely, Ag⁺, with long-effective antimicrobial properties, and Zn²⁺, as an essential trace element, are being considered for use in the future as multifunctional IUDs. The purpose of this study was to assess the cytotoxicity of these metal ions and their mixtures on primary human endometrial epithelial cells (HEECs) cultured in vitro and to provide several choices of alternative potential materials for creating excellent IUDs in the future.
With the use of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-formazan (MTT-f) production, the cytotoxic effects of single metal ions (Cu²⁺, Zn²⁺, Ag⁺) on HEECs after exposure for 24, 48 or 72 h were investigated, and the synergistic and antagonistic effects of two ions applied simultaneously were also assessed.
The cytotoxicity of the metal ions on HEECs ranked as follows: Ag⁺>Cu²⁺>Zn²⁺. All combinations of those tested indicated that the Cu²⁺+Zn²⁺ system exhibited an antagonistic effect absolutely, the Zn²⁺+Ag⁺ system showed both antagonism and slight synergism, and asynergistic effect was observed in the Cu²⁺+Ag⁺ system.
From a perspective of favorable biocompatibility, Zn²⁺ and the Cu²⁺+Zn²⁺ mixture showed evidence of potential components for use in future IUDs. Although having strong cytotoxicity, Ag⁺ with its low release rate and broad-spectrum antibiotic activity may also be considered. The study also demonstrated the relative stability of Cu²⁺ as a classic material of IUD.
The copper/low-density polyethylene composite (Cu/LDPE composite) intrauterine devices (IUDs), which can eliminate or lessen the side effects of existing IUDs, have been developed in our laboratory. As a novel type of copper-containing IUDs, it is not clear whether the mechanical properties of the Cu/LDPE composite IUDs can meet the need of clinical use or not. Therefore, the mechanical properties of the Cu/LDPE composite IUDs have been studied in the present article.
The influence of copper particle content and size on the mechanical properties of the Cu/LDPE composite IUDs was analyzed firstly to provide guidance for the material composition design of the Cu/LDPE composite IUDs, and then the BaSO(4)/LDPE composite, which has been applied as a framework of the existing copper-containing IUDs in clinical use for decades, has been used as reference to judge whether the mechanical properties of the Cu/LDPE composite IUDs can meet the need of clinical use or not. However, the mechanical properties of IUDs cannot be characterized directly. Therefore, the mechanical properties of both the Cu/LDPE composite IUDs and the framework of the existing copper-containing IUDs were investigated by means of tensile test using standard tensile samples, and the fracture surface morphology of the tensile samples was characterized by scanning electron microscopy (SEM).
Both the elongation at break and the tensile strength decrease with increasing of copper particle content and increase with increasing of the copper particle size, while the elastic modulus shows an opposite tendency. The tensile strength and elastic modulus of both the Cu/LDPE microcomposite IUDs and the Cu/LDPE nanocomposite IUDs with 25 wt.% of copper particles are higher than those of existing copper-containing IUDs (TCu220C; its framework is made of the BaSO(4)/LDPE composite with 20 wt.% of BaSO(4)).
The content and size of the copper particles have significant effect on the mechanical properties of Cu/LDPE composite IUDs. The mechanical properties of both the Cu/LDPE microcomposite IUDs and the Cu/LDPE nanocomposite IUDs with 25 wt.% of copper particles were superior to that of existing copper-containing IUDs, indicating that the novel Cu/LDPE composite IUDs can satisfy the requirement of mechanical properties in clinical application.
Copper/low-density polyethylene (Cu/LDPE) nanocomposite intrauterine device (IUD) is an implanted medicinal device that must be sterilized before use. Sterilization processes act either chemically or physically, leading to a lethal change in the structure or function of organic macromolecules in microorganisms. Given the nature of their action, sterilization might also attack the macromolecules of polymers by the same mechanisms, resulting in changes in surface functional groups and in the internal structure of the polymer. If sterilization leads to changes in surface functional groups and in the internal structure of the LDPE matrix, which will influence the mechanical property and cupric ions release rate of novel Cu/LDPE nanocomposite IUDs, potential clinical application will be limited. Therefore, it is necessary to study the influence of ethylene oxide sterilization on the potential clinical application of novel Cu/LDPE nanocomposite IUDs.
The influence of ethylene oxide sterilization on the internal structure, surface functional groups, mechanical property and cupric ions release rate of novel Cu/LDPE nanocomposite IUDs was studied using differential scanning calorimetry, attenuated total reflection Fourier transform infrared spectroscopy, tensile testing and absorbance measurement.
Ethylene oxide sterilization did not have any influence on the internal structure, surface functional groups, mechanical property and cupric ions release rate of novel Cu/LDPE nanocomposite intrauterine devices.
Ethylene oxide sterilization will not affect the potential application of novel Cu/LDPE nanocomposite IUDs.
Contraception as a socially aceptable custom is by and large a 20th century phenomenon and is now perceived by many as a solution to a pressing world problem - that of overpopulation. As Shakespeare states in quotations above, we can define accurately what we would like to accomplish, but the achievement is often easier said than done. Such sentiments describe very well the state of the art as far as contraception is concerned. Most thinking people, and indeed many governments, see a reduction of the birth rate as the most significant way to achieve economic progress and to raise the standard of living in their countries commensurate with the expectations of their citizens. It is clear that we, the peoples of the world, have a choice, either we can reproduce until resources become insufficient to support us or we can take steps to control reproduction and achieve the desirable goal of zero population growth. Zero growth is defined as that state where the number of births and deaths are equal.
Two copper 7 intrauterine devices were found to be devoid of copper on removal after 55 and 63 months of use respectively. The implications of this observation are discussed in relation to data regarding the useful lifespan of such contraceptive devices.
Epicutaneous tests with copper, nickel and cobalt were performed in 37 patients using copper IUD who had shown side-effects to the IUD. None of them was allergic to copper; four were allergic to nickel and one to cobalt. Metal allergy was not considered to be the cause of the side-effects in any of the patients.
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.
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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.
The influence of corrosion on the copper wire in the Copper T-200 intrauterine device (IUD) was studied in devices which had been in utero for 3 to 52 months. This was done mainly by examining cross-sections of the wires under a light microscope. Corrosion was normally localized to narrow areas and led to breakage and fragmentation of the copper wire. Neither deposits on the wire nor corrosion products prevented the dissolution of the copper. The progress of the corrosion over a given time was determined by comparing the depth of corrosion with the original dimension of the wire. The lifetime of the IUD was evaluated on the basis of the progress of corrosion, the calculated copper release, and the number of cases of wire breakage. It was found that the Copper T-200 could be left in place for up to 45 months.
We measured the rate of release from copper-bearing intrauterine contraceptive devices (IUDs) with varying copper surface areas. Over 135 days of observation the release rate decreased exponentially. This decrease in the release rate was associated with the deposition of a protein layer on the surface of the metal. The bioavailability of copper on IUDs was not related to the volume of copper remaining on the device. Consequently any increase in the copper surface area of an IUD is unlikely to affect the duration of its copper-dependent contraceptive action.
The rate of copper loss from bright and tarnished collars from Copper T Model TCu 380A IUDs has been investigated in amino acid solutions of pH 5.5 and 7.4 and in serum. In all three media, the tarnished collars quickly became bright and lost copper at the same rate as the initially bright collars. The single exception was when a high ratio of copper surface to serum was used. Under those conditions the tarnished collars initially became bright but after two days a black precipitate appeared on both the initially bright and tarnished collars and weight loss ceased. When a higher ratio of serum to copper surface was used, the pattern was one of continuing loss although at a lower rate than in the amino acid solutions. It is concluded that tarnish does not compromise the oxidation and dissolution of copper even in serum. Serum is considered a surrogate for uterine fluid.
The mechanism of action of intrauterine devices varies from one type of device to another, although the principle of action is the same, namely, to interfere with the physiology of reproduction at the endometrial level. The biochemical changes of the endometrial tissue and the composition of the uterine fluid have been reviewed in relation to the use of inert, copper-medicated and steroid-releasing IUDs. All IUDs, whether inert or medicated, provoke a significant increase in the number of neutrophils, mononuclear cells and plasma cells, the presence of which is unrelated to the tissue infiltration of inflammatory cells occurring pre-menstrually of the normal menstrual cycle. The increase of leucocytes in IUD-users is compatible with a foreign body reaction which may be related to the antifertility effect. The addition of copper to an inert IUD has been shown to significantly alter the metabolism of the endometrial cells, e.g. the enzymatic activity and the DOVA-synthesis. The steroid-medicated IUDs represent a new approach to intrauterine contraception where the morphology of the endometrium is considerably altered, showing massive decidual changes, atrophic glands and sometimes atrophy of the whole functional layer. In addition, there is an important foreign body reaction, similar to that of the inert IUDs. The enzymatic activity, as well as the proliferative activity was significantly altered in the endometrium of these IUD-users. Changes in the endometrial fibrinolytic activity in IUD-users have been demonstrated to be related to the presence of irregular bleeding. Micro-traumata of the endometrium and the increased fibrinolytic activity may also interfere with the protective processes present in the physiologically normal endometrium. Further studies on the factors influencing the fertilizing ability of the spermatozoa in the female genital tract, as well as on the conditions of the human endometrium required for the implantation of a blastocyst, may yield important information for the improvement of intrauterine contraception.
The effect of cupric ions on the human uterus and the involvement of prostaglandins (PGs) in mediating this effect was studied by recording of isometric contractions of isolated myometrial strips and pieces of uterine arteries, and by intrauterine pressure recordings in women before the onset of menstruation. In vitro, CuCl2 in concentrations of 10(-4) M and higher caused a significant inhibition of myometrial contractile activity, but no effect on the artery preparations was seen. Furthermore, the contractile response of myometrial strips to PGF2 alpha and PGE2 (10 ng/ml) decreased in the presence of CuCl2 in concentrations of 5 and 50 mumol. In vivo, instillations of 0.3, 1.0 and 2.0 mM of CuCl2 in 0.7 ml of saline solution into the uterine cavity caused a dose-dependent stimulation of uterine activity, but after pretreatment with naproxen, 500 mg orally, the effect of these substances was abolished. After naproxen treatment, but during infusion of PGF2 alpha (5 micrograms/min), the response to the CuCl2 solutions was partially restored. It is suggested that cupric ions, at high concentrations, have an inhibiting effect on myometrial activity. The stimulatory effect of low doses of CuCl2 seen after instillation into the uterine cavity is largely exerted via initiation of synthesis and release of endometrial PGs.
The rate of copper loss from 329 IUDs (Multiload Cu250, TCu-220C and Cu7) which had been terminated for various reasons after 0.5-46 months in-utero were determined. All 3 IUDs showed a wide scatter of release rates with no significant differences between the ML Cu250 and the Cu7. The TCu-220C showed the highest rates and in contrast to the ML Cu250 and Cu7, the decrease with time was not significant. Its rate of copper loss was significantly higher than the ML Cu250 in the 1st year, but comparable after that. The TCu-220C had a similar rate to the Cu7 in the 1st year and significantly higher rates subsequently. The relevance of these findings to observed pregnancy rates and area of copper on the IUDs is discussed.
An alternative method of male contraception is crucial at this stage of increasing population in the developing world. A non-obstructive, non-hormonal, reversible method of male contraception would find acceptance in oriental communities. Our experience with copper IVD in small animals has been encouraging. We present here an extension of the use of the copper IVD in the rhesus monkey. Treated male rhesus ejaculate showed fifteen-to thirty-five-fold increase in copper levels up to 10 months after insertion of Cu IVD . Semen analysis showed an increase of dead sperm (23.0% - 52.3%; control 4.5% - 14.0%) and decrease in percentage of motile sperm (10-30%; control 70-80%). Fertility studies using treated male rhesus of proven fertility from the breeding colony mated with cycling females of proven fertility showed highly significant reduction of fertility up to 13 months (P less than 0.001). Reduction in fertility of the treated rhesus was also significant up to a period of 23 months (P less than 0.01). A reversal of contraceptive effect and increase in sperm count and motility is observed after 13 months post-treatment. Studies are required to achieve an increase in the effective life span of the IVD .
Although the effective life span of an IUD provided with filamentous copper is, calculated on the basis of the rate of dissolution of copper, several years, corrosion may lead to breakage of the wire after a shorter period of use. When copper wire with a diameter of 0.20 to 0.25 mm is used, the proportion of IUDs with broken wires increases with time after three years of use. It was not known whether this disadvantage could be reduced or eliminated by the use of a thicker wire. In this study the corrosion behaviour was observed in MLCu250 and MLCu375 devices, which have copper wire with a diameter of 0.30 and 0.40 mm, respectively. The earliest breakage was observed after 8 months of use for 0.30 mm wire and after 9 months of use for 0.40 mm wire. In IUDs with 0.30 mm wire the proportion with broken wires increased after 3 years of use. Since examples of the MLCu375 with 0.40 mm wire used for more than 3 years were few, it was impossible to make definite conclusions in this respect. In general, the corrosion behaviour in copper diameter range of 0.3 to 0.4 mm is the same as indicated in previous studies for diameter range of 0.2 to 0.25.
It has been shown previously that supplementing plastic intrauterine devices (IUDs) with copper wire enhances the antifertility effect of the device. The use of copper intrauterine contraceptive devices, however, is currently limited to two to three years, mainly because of wire fragmentation, which was observed as early as after eight months of use. In the resulting search for a long-lasting device, two new systems of duplex wire, with gold and platinum cores electrolytically coated with copper, were devised and studied. Initially, duplex wires and controls were exposed to physiological solution. Copper dissolution rate and corrosion morphology were studied by weight-loss measurements and optical metallography. Similar systems were then surgically implanted in rat uteri for varying periods of up to 26 weeks. Electron microanalysis of corrosion products, in addition to weight-loss measurements and metallography, was performed. The results showed that a uniform and ductile copper coating is obtainable by electroplating on gold and platinum wires. Rate of copper dissolution is similar to that of solid copper wire. No dissolution of gold and platinum in the controls or coated wires was detected by weight loss, metallography, or atomic absorption measurements. Microanalysis of the deposits and corrosion products on the wires in the uteri environment showed sulfur, chlorine, and calcium, in addition to copper. The results of this study suggest that supplementing IUDs with copper-coated gold or platinum wires may result in significant prolongation of the life span of the device by preventing uncontrolled loss of copper caused by wire fragmentation.
The influence of copper ions on myometrial activity was tested in nonpregnant rabbits in vitro and in vivo, and nonpregnant women in vivo. In an organ bath, CuCl2 in concentrations of 3 micro M and higher caused a dose-dependent increase in the contractile activity of isolated rabbit myometrium. In rabbits in vivo, intrauterine instillations of 0.2 to 2 mM of CuCl2 in 0.6 ml of saline solution caused a dose-dependent increase of myometrial activity in the uterine horn where it was injected, and the response lasted up to 30 minutes. The activity in the other horn remained unchanged and control injections with saline had no effect. Also, in nonpregnant women, a clear and dose-dependent effect of 1 ml of 0.3 to 3 mM of CuCl2 dissolved in saline was observed after intrauterine instillation. Saline itself in the same volume had no effect. It is estimated that the intrauterine doses of copper which were used in these experiments lead to Cu++ concentrations in the uterine tissues which were similar to those in women carrying a copper IUD, and it is suggested that the copper from such IUDs might have effects on myometrial activity contributing to the contraceptive action and to some of the side-effects of these devices.
The use of copper intrauterine contraceptive devices is currently limited to 2-3 years, mainly due to wire fragmentation, which was observed as early as after 8 months of use. In the resulting search for a long-lasting device, two new systems of duplex wire, with gold and platinum cores electrolytically coated with copper, were devised and studied. Initially, duplex wires and controls were exposed to physiological solution. Copper dissolution rate, and corrosion morphology were studied by weight-loss measurements and optical metallography. Similar systems were then surgically implanted in rat uteri for varying periods up to 26 weeks. Electron microanalysis of corrosion products in addition to weight-loss measurements and metallography was performed. The results showed that a uniform and ductile copper coating is obtainable by electroplating on gold and platinum wires. The rate of copper dissolution is similar to that of solid copper wire. No dissolution of gold and platinum in the controls or coated wires was detected by weight loss, metallography or atomic absorption measurements. Microanalysis of the deposits and corrosion products on the wires in the uterine environment showed the presence of compounds containing sulphur, chlorine, calcium and copper. The results of this study suggest that supplementing IUDs with copper-coated gold or platinum wires may result in significant prolongation of the life-span of the device by preventing uncontrolled loss of copper caused by wire fragmentation.
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.
Experiences based on 2689 first insertions of the Copper-T-200 and follow-up of every patient for more than 12 months are reported. The first segment net cumulative rates for the first year by type of termination were pregnancy 1.6, expulsion 2.2, removals 7.1, and continuation rate 89.2. The loss to follow-up at 12 months was 3.8 percent.It seems that the use-effectiveness of the copper-T-200 is influenced by the insertion technique. In this study, special attention was paid to fundal insertion of the IUD. This may have contributed to the low expulsion and removal rates and the high continuation rate observed. During this study, no uterine perforation was observed.
The life-table analysis of about 16,000 first insertions of the Copper T Model 200 (TCu-200) in the United States indicates that about 58.5 percent of these women terminated the use of the TCu-200 by the end of three years following the insertion. This includes about 6.6 percent who became pregnant during this period. The results of the TCu-200 are compared with the Copper 7 and with Dalkon Shields from two double-blind studies of these devices. In the end, the index — The Mortality Benefit Ratio — defined in terms of the number of deaths per 1000 births averted, is used to compare the relative risks and benefits associated with various forms of contraception. Based on the experience in the United States, the values of the Mortality Benefit Ratio indicate that IUDs are at least as safe, if not safer, than other forms of contraception currently available.
Rings, loops, spirals, coils, bows, M's, Dalkon Shields, Copper Ts, Cu 7s, intrauterine membranes, and fluid filled devices, an almost infinite variety of intrauterine devices are now available in different parts of the world in a vast array of sizes, shapes, and materials. How many IUDs are now in use? Which is best for the individual woman? Which is best for national family planning programs? What are the main problems in clinical use? What are the most significant improvements in IUD design? In short, what is the present role and future potential of the intrauterine device in the management of fertility? A little more than a decade after intrauterine devices were reconsidered as medically acceptable these questions remain. Undoubtedly, intrauterine devices have become important elements in modern contraception. If they do not quite live up to their original promise as 'the ideal contraceptive', they are nevertheless highly effective and widely used. In spite of extensive clinical study of many IUD configurations and a 'reasonably good' evaluation methodology, the effort to improve intrauterine contraception has proved expensive and frustrating. Research priorities identified by various IUD investigators include: better understanding of exactly how IUDs function so that design changes can be made on the basis of knowledge rather than randon experimentation; better criteria for evaluation of bleeding and pain since removal rates may be influenced by factors not related to the device such as attending personnel and cultural inhibitions; additional randomized comparative studies of IUD models conducted in single clinic settings and including reinsertions and experience over extended time periods; field trials directed toward hypothesis testing, that is, altering individual IUD characteristics to investigate their effects on changing performance; better indentification of cultural, racial, anatomical, nutritional and other factors that may influence IUD performance so that where possible the appropriate IUD can be chosen for each woman; establishment of an international data bank compiling and analyzing IUD data from clinical research centers throughout the world; development of simpler IUD insertion techniques and training in these techniques so that nonphysicians with minimal education, including rural village midwives, can safely and effectively insert devices.
PIP
An investigation to develop and study duplex wire for use in IUDs was initiated by the observation that copper wires wound on IUDs occasionally fragmented after prolonged in vivo use. The duplex wires consist of an exposed active copper surface plated onto an inert inner core to maintain structural continuity. Data demonstrated that the dissolution rates as well as surface changes and biological effects are independent of whether stainless steel, Inconnel or Tophet-M was used as the core. Small IUDs can be wound with a duplex wire in a manner identical to that presently used with pure copper to resist fragmentation and to provide contraceptive effects.
Some of the biological aspects of copper relevant to reproductive processes are reviewed. Included are cyclic variations in the concentrations of copper in the endometrium, uterine fluid, cervical mucus, and serum as modified by the presence of intrauterine metallic copper and after its removal. Variations in the endometrial enzymes, namely, α-amylase, glycogen synthetase, and phosphorylase, are also considered. The rate of copper loss from the intrauterine copper T in the woman is reviewed, and these data are considered in relation to the duration of effective antifertility action within the uterus. In addition, the theoretical participation of this quantity of copper in the total body metabolic balance of copper is considered. Special reference is made to Wilson's disease. Examples of surface changes in the copper wire which may occur during its intrauterine life are described. The potential implications of copper fragmentation are considered, and relevant experimental data obtained from rhesus monkey studies are presented. The latest clinical data on use-effectiveness of the copper T Models 200 and 300 in nulligravidous, nulliparous, and parous women in the United States and abroad are presented. In addition, a preliminary report is made on a double-blind comparison of the T Cu 200 and the Copper 7 after 9 months of use.
Our previous experience with the copper T200 (TCu-200) in 2,689 women after 12 months' follow-up of every patient showed that the use-effectiveness of this device is high. The effect of increasing the copper-releasing area by 50 per cent has now been studied. The same polyethylene T-device was used as the intrauterine carrier for copper wire, but the surface area was increased to 300 sq. mm. The first-segment net cumulative event rates with this intrauterine contraceptive device, the copper T300 (TCu-300), in 1,420 women during the first year of continuous use were as follows: pregnancy, 1.0; expulsion, 1.3; all removals, 7.3; bleeding and/or pain, 4.3; and continuation rate, 90.4. The loss to follow-up at 12 months was 6.1 per cent. No uterine perforation was observed. When the results were compared with those obtained in our previous TCu-200 study, where the same physicians performed the insertions, it seemed that the pregnancy and expulsion rates were lower with the TCu-300, but only the difference in the expulsion rate was statistically significant, the continuation rate being equally high with either device.
Published and unpublished data, 1971–1974, on copper intrauterine devices are reviewed. Based on results of 16 clinical reports, the copper T and copper 7 devices are shown to have net cumulative pregnancy rates of approximately 1–2 (range 0–3) per 100 woman-years after one year of use. The problem of increased menstrual bleeding following insertion is less with copper IUDs than with either the Lippes loop, Saf-T-Coil, or Dalkon shield. Data and evaluation so far suggest that nulliparous or low parity women in countries where follow-up medical care is available will be the principal beneficiaries of this new contraceptive method.
Copper-T devices (T-Cu 200) used for different periods of time were submitted to metallographic analyses and sperm penetration tests in order to determine whether there is a time-linked effect. In our clinical experience with the mentioned device, we have observed an increase of the pregnancy rate after the 12th month of use.A linear copper release of some 20 μg/day was measured during a period of 14 to 840 days showing that copper release and copper corrosion are not parallel.In contrast to metallic copper-T devices, used corroded devices were not capable of inhibiting sperm motility .
Although the data presented are relatively preliminary, the efficacy of metallic copper as an adjunct to an inert intrauterine device seems to be well established. The addition of copper to an IUD will probably increase its contraceptive action but is unlikely to reduce significantly the side effects that are caused by compression of the endometrium and distention of the myometrium. The development of the copper T and, subsequently, the copper 7 has provided locally acting effective contraception for the nullipara and nulligravida as well as for the traditional parous woman.
The Copper-T-200 intrauterine contraceptive device was inserted immediately after legal abortion in 154 women. Early complications (during the operation and within the first eight postoperative weeks) were recorded and compared with those of a control group of 144 women having abortion only. Insertion of the IUD neither increased the incidence or severity of early complications nor lengthened the stay in hospital after the abortion. The first segment net cumulative event rates among the patients receiving the TCu-200 were analyzed by the life-table method after twelve months and again after eighteen months of use. At twelve months, the pregnancy rate was 3.3, the expulsion rate 0.0 and the rate of removal for medical reasons 11.1. At eighteen months, the corresponding rates for pregnancy, expulsion and medical removals were 3.3, 0.7 and 13.1, respectively.
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).
PIP
The copper T (TCu) intrauterine device (IUD) has been found to be an effective and well tolerated method of contraception for nulliparous women. Tatum theorized that his TCu's effectiveness was directly related to the amount of copper used. 471 nulliparous women had the TCu 200 device inserted; 347 nulliparous women received the TCu 300; 785 nulliparous women had the TCu 380 inserted. (The figures indicate the sq mm of copper surface area in each device.) Discontinuation rates at 12 months were 25.8, 19.3, and 18.1 per 100 women respectively. Respective pregnancy rates were 1.7, .6, and .2 per 100 women at 12 months. The results of this study suggest that the effectiveness in pregnancy prevention is greater with increased amounts of copper.
PIP
605 women were inserted with plain T-IUDs, 508 patients were inserted with TCu-A devices, and 279 women were inserted with TCu-B devices. In the TCu-A, a 2 cm length of copper wire of .5 mm diameter was wound around the upper aspect of the vertical arm of the T-IUD. In the TCu-B, a 6 cm length of wire of .15 mm diameter was coiled downward over a 1 cm distance. The surface area of copper was 30 mm in both prototypes. The data derived from the 3 series of patients were tabulated and analyzed utilizing the Life Table method of Tietze. Endometrial biopsies were obtained from randomly selected patients. Results showed that after 2 years of use, the plain T device had a significantly lower rate of metrorrhagia than had been reported for any other contraceptive device. The rate was approximately 6 times less than that observed with the Lippes loop D. Pain was a negligible cause for closure during the 2 year period. The T device had a rate of pregnancy of 24.3 which is 6 times the pregnancy rate of the Lippes loop D. The first expulsion rate was 4.5, but the rate for later expulsions was .4. When a small qlantity of copper was added to the T there was a dramatic and highly significant reduction in the rate of pregnancy. At the end of 2 years of use the rate was 9.8 for the TCu-A. Other clinical parameters also were apparently modified by the metallic copper. The expulsion rate was reduced, the rate of metrorrhagia was slightly increased, and the rate of pain may have been increased. During the same lenght of time the rate of removal for loop D because of bleeding and/or pain is approximately 3 times greater than for the T with copper. Reductions in both expulsion and removal rates of TCu because of medical reasons constituted the principal factors accounting for the continuation rate of 77.6 as compared with 65.6 for loop D at the end of 2 years of use.
Clinical evaluation of the contraceptive effectiveness of the endouterine copper "T" has been extended to include "T" devices bearing copper wire having surface areas of 120 mm.2 and of 200 mm.2 copper, respectively. Within the range studied, the antifertility effect increases as the area of the exposed surface of copper is increased. At the end of one year, the TCu-120 resulted in a pregnancy rate of 2.0 per 100 users and a continuation rate of 94.1 per cent. Results from 7 months of observation with the TCu-200 showed a pregnancy rate of zero and a continuation rate of 98.3 per cent.
Effect on trace elements in the endometrium, cervical mucus and plasma Immediate postabortion insertion of the Copper-T (TCu-2O0) with eighteen months follow-up Textbook of quantitative inorganic analysis
- K Hagenfeldt
- H Timonen
- T Luukkainen
- I Kolthoff
- E Sandell
Hagenfeldt, K.: Intrauterine contraception with the Copper-T de-vice. l. Effect on trace elements in the endometrium, cervical mucus and plasma. Contraception 6:37-54 (1972) Timonen, H. and Luukkainen, T.: Immediate postabortion insertion of the Copper-T (TCu-2O0) with eighteen months follow-up. Contra-ception 9:153-160 (1974) Kolthoff, I. and Sandell, E.: Textbook of quantitative inorganic analysis. Revised Edition, The Macmillan Company, New York, 1949, pp. 630-632
Copper IUDs: A review of the literature IUDs reassessed -A decade of experience
- A Jain
- B Orlans
- S Huber
- P Piotrow
- B Orlans
- G Kommer
Jain, A.: Safety and effectiveness of intrauterine devices. Contra-ception 11:243-259 (1974) Orlans, B.: Copper IUDs: A review of the literature. Contraception 10:543-559 (1974) Huber, S., Piotrow, P., Orlans, B., and Kommer, G.: IUDs reassessed -A decade of experience. Population Reports, Series B, No. 2, Washington D.C., George Washington University Medical Center, Popu-lation Information Program, January 1975.
Die kanzerogene Wirkung von Arsen und Nickel
- Konetzke
Multiclinic Copper-T studies in Finland
- Luukkainen