Contraception with intrauterine devices.

PIP: A review of the history of contraception with intrauterine devices, characteristics of present devices, and directions of current research is presented. The serious need for population control is not yet being met by today's inconvenient, ineffective, or unsafe methods. Intrauterine devices have been best for international family planning programs because they are cheap, easily installed, and provide continuous protection. There are many different models that have been and are being used, with different effectiveness and complication rates. The most commonly used today is the Lippes Loop, with a pregnancy rate of 2.8/100 years of woman use and an expulsion rate of 10.4. Most of these failures occur in the first few months of use, after which these rates are greatly reduced. The removal rate because of bleeding or pain for the Lippes device is 14.0. Other devices commonly used have pregnancy rates ranging 1.3-4.7, expulsion rates of 2.6-25.8, and removal rates of 13.5-22.1. Expulsion is directly related to the size and design of the IUD and the age and parity of t,e recipient. It is important to match the size of the device used to the individual characteristics of the patient. Research is seeking a design that will implant itself in the endometrium to resist expulsion, but not too deeply so that it is covered. Removal for bleeding and pain remains the most frequent complication of the IUD, and it partly depends on the skill of the inserting physician and how well the patient is psychologically prepared for side effects in the first months of use. Pregnancy is the most significant IUD complication. The key to an effective IUD is an understanding of its antifertility mechanism, which has thus far eluded researchers. The IUD prevents implantation of the blastocyst in the uterine wall, which may be due to a foreign-body reaction in the endometrium. IUDs with copper cause a greater reaction than plastic devices and provide hope for a very effective device; particularly the T-shaped design, which resists expulsion. The most promising new IUD is the Dalkon Shield. It has small projections that imbed in the endometrium and a broad surface for contact with the uterine wall. In preliminary experiments the pregnancy rate with this device was 1.1, the expulsion rate 2.3, and the removal rate 2.0, much lower than that with any other device yet developed. It is concluded that IUDs such as the Dalkon Shield can provide safe contraception with high effectiveness.^ieng

Pseudo-sulfur granules associated with intrauterine contraceptive devices.

A structure resembling a sulfur granule found in histologic sections of endometrium from patients with intrauterine contraceptive devices is described. It is distinguished from a true sulfur granule on morphologic grounds and is further characterized as a foreign substance, most probably fragments of the synthetic contraceptive device. It is not associated with clinical disease. Microbiologic cultures of removed intrauterine contraceptive devices show no consistent or predominant growth pattern.

PIP: Microscopic slides of 235 samples of endometrial curettings obtained when an IUD was removed were reviewed for the presence of sulfur granule-like structures and IUD-associated material. Where such structures were present, the following stains were done: Gram, Ziehl-Neelsen, periodic acid-Schiff, Grocott's modification of Gomori's methenamine silver, and von Kossa's stain for calcium. A prospective study was conducted in an effort to determine a possible microbiologic origin of the "granules." 50 IUDs removed at the time of dilatation and curettage were cultured. The technics used are described. In 235 endometrial samples examined histologically, 17, or 7.2%, showed the presence of granular structures. 1 true actinomycotic granule was identified. There were 16, or 6.8%, examples of pseudo-sulfur granule; 71 endometria (30%) contained IUD-associated material. All of the pseudo-sulfur granules were found in samples containing the IUD-associated material. The finding of IUD associated material and granules was not related to the type of IUD that was removed. On histologic examination, the most common type of sulfur granule-like structure found showed a glassy eosinophilic color, a radiate appearance, and peripheral clubbing. 14 (28%) of the IUDs cultured yielded no growth, and 17 (34%) grew normal vaginal flora. 19 of the cultures yielded a variety of organisms not normally considered part of the vaginal flora; there was no association with a particular type of IUD. Of the 50 IUDs cultured, 3 had pseudo-sulfur granules in the histologic sections of the corresponding endometrial curettings. 33% of patients with pseudo-sulfur granules and 52% of patients without these granules sought removal of the IUD because of symptoms. The most common type of granule encountered is classified as a psuedo-sulfur granule and is nonpathogenic.

The peritoneal reaction to the translocated copper intrauterine device in women and female rats.

The observation of a very severe peritoneal reaction to translocated copper-bearing devices in five women necessitated operative removal. Three Copper-T (Ortho Gyne-T, Ortho, Saunderton, High Wycombe, England) and two Copper-7 (Gravigard, Searle, High Wycombe, England) devices were involved. Similarly severe peritoneal reactions were noted in 90% of female rats who had small-sized modified copper devices inserted into their peritoneal cavities. In a control group of rats with the same device but without a copper wire, mild adhesions were observed in the majority (85%), and none had a severe peritoneal reaction. It seems evident that the severe peritoneal reaction is induced by the copper wire in both women and female rats.

PIP: The translocation of an IUD from the uterus to the peritoneal cavity is an uncommon but important complication of IUD use. The peritoneal reaction to translocated copper devices is much more pronounced than the reaction to inert devices. The contribution of the copper is investigated after 5 women with translocated copper IUDs were treated by the authors for serious involvement of the peritoneum. In 20 female albino rats, modified (adapted to the size of the animal) copper-bearing IUDs were inserted into the peritoneal cavities. In an additional 20 rats, the copper was removed from the devices before insertion. In 5 rats, only an incision was made. The animals were sacrificed after 14 days. In the copper device group, 90% of the animals had severe adhesions, while in the inert device group, no severe adhesions were noted, 10% had moderate adhesions and 85% had mild reactions. Reactions were absent in the laparotomy only group. The peritoneal reaction to the copper devices was severe in this experimental study, and is consistent with other case reports and the authors' clinical experience. Copper IUDs that are translocated should be removed as soon as possible after diagnosis to minimize their harmful effect. Removal by laparoscopy should be attempted before peritoneal involvement; by laparotomy thereafter.

The effect of intrauterine devices containing zinc and copper on their levels in serum.

Serum levels of copper and zinc were determined in 11 health women in whom Latex Leaf intrauterine devices (IUDs) containing copper and zinc had been inserted. Patients with low levels of serum copper or zinc before insertion usually had increased levels of either of these metals while using the device, but they did not exceed the upper limits of normal values. When the group was considered as a whole, the serum levels of zinc showed a slight tendency to increase with duration of IUD use, whereas there was no statistical difference between the serum levels of copper before and after insertion of the IUD.

PIP: Serum levels of copper and zinc were measured in 111 healthy women in whom Latex Leaf IUDs containing copper and zinc had been inserted. The women ranged from 21 to 41 years of age. Months of use ranged from 1 to 23 with an average of 14.6. The 1st blood sample was obtained before insertion and the 2nd from 1 to 19 months after insertion. Mean level of serum copper in the 1st sample was 1.42 mcg/ml. Age and parity had no effect; a slight tendency for higher levels was observed only in multigravidas. There were no significant changes in mean copper levels even when the levels were correlated with duration of usage. Mean serum zinc level before insertion was 1.1 mcg/ml with no correlation to age, gravidity, or parity. The 2nd sample showed a slight increase, 109% + or -3.25% standard error p .005. This increase correlated with the time the device was in situ. In general, patients with low levels of serum copper or zinc before insertion usually had increased levels after use but these levels did not exceed the upper limits of normal values. This may be due to an initially low level of the copper fraction bound to serum albumin and indicates the existence of some equilibrium between free and bound metal in the system.

Experience with two different medicated intrauterine devices: a comparative study of the Progestasert and Nova-T.

A comparative study of the Progestasert (UPS) and the Nova-T in 326 randomly selected women was carried out. The observation period was 1 year. The over-all continuation rates for the two types of intrauterine devices (IUDs) were similar. The expulsion rate for the Nova-T (9.2%) was considerably higher (P = 0.001) than that for the UPS (1.2%). Medical removals for bleeding/pain were more frequent (P = 0.028) for the UPS (15.4%) as compared with the Nova-T (6.1%). The pregnancy rate for the UPS (Pearl index = 4.8) was insignificantly higher than that for the Nova-T (Pearl index = 2.8). Two of the pregnancies in the UPS group were ectopic. No significant changes in the reactive immunoglobulins (IgA, IgG, or IgM) were observed in either of the groups. Our results indicate that neither of these two IUDs is preferable to the already existing medicated IUDs, such as the Copper T or the Copper 7.

PIP: This study 1) compared the efficacy and continuation rates for the Progestasert (UPS) and Nova-T (Y-shaped, copper-medicated, 200 sq. mm., with flexible arms) and 2) determined the serum immunoglobulin response to women wearing 1 of these 2 differently medicated IUDs. Overall continuation rates for the 2 types of IUDs over a 1-year observation period (UPS must be changed yearly) were similar. Expulsion rate for Nova-T (9.2%), however, was considerably higher (P=.001) than for the UPS (1.2%). Pregnancy rate for the UPS by the Pearl index was 4.8 and was insignificantly higher than that for Nova-T (Pearl index=2.8). 2 UPS pregnancies were ectopic. Removals for bleeding/pain (i.e., medical removals) were more frequent (P=.082) for UPS (15.4%) than for Nova-T (6.1%). No significant changes in reactive immunoglobins (Igs), i.e., IgA, IgG, or IgM, were observed in either IUD group. Results suggested that neither IUD was preferable to already existing medicated IUDs.

Serum copper in long-term users of copper intrauterine devices.

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.

PIP: This study was performed to determine whether long-term use of copper IUDs was associated with any alteration in serum copper levels in users. These studies had both cross-sectional and longitudinal components, with the cross-sectional aspect covering 148 controls and 202 women who used either the Lippes loop (n=95) or the copper T 200 (n=107) for 6-48 months. The longitudinal aspect was carried out in 7 women not using any form of contraception and in 17 women who had had a copper IUD inserted; serial copper levels in serum were measured every 3 months for 24 months. The aim was to ascertain any danger of copper toxicity with copper-medicated IUD use. Serial estimations in copper IUD wearers showed that there was no alteration in serum copper levels for up to 24 months. The mean range and frequency distribution of serum copper levels in long-term copper IUD wearers were similar to those seen in the normal (control) population. In addition, there was no difference in the mean 24-hour urinary copper excretion between the control group and copper IUD users. The results verified the first hypothesis of the researchers, that copper released from a copper IUD is not readily absorbed.

Concentrations of copper in human secretions and weight of the copper wire during the 4 to 7 years after insertion of a Cu-IUD (intrauterine device).

The useful life span of the two most commonly used copper intrauterine devices (Cu-IUDs) (Gravigard and Cu-T) was investigated in a long-term study up to 90 months after insertion. Minor differences between the two types of devices were found that, however, probably do not contribute to a diverging contraceptive efficacy with time. To be able to ensure maximal contraceptive effect, the authors suggest on the basis of the present data that the time of use not exceed 5 to 6 years.

PIP: This Swedish study assesses the useful life span of copper intrauterine devices (Cu-IUDs) beyond the recommended 3 years to between 4-9 years. The subjects consisted of 109 regularly menstruating women (para, 0-4; ages, 18-46) who had voluntarily used a Cu-IUD for 43-90 months. Uterine secretions were collected with a urethral catheter before the Cu-IUD was removed or replaced. Secretions varied in amount from 0.7-10.3 gm and were collected on days 8-23 of the cycle. Copper content was measured by atomic absorption spectroscopy and the copper wire weighed. Results indicate no significant differences in: 1) copper concentrations after 4 years of use, 2) the copper concentrations in uterine secretions of women using Gravigards and Cu-Ts, 3) secretions obtained during cycle days 8-14 in comparison with cycle days 15-23, and 4) weights over time between the two devices. The study also found a decreasing concentration of copper during the period of 43-87 months after insertion of Cu-IUDs. With reference to copper ion concentrations, the contraceptive efficacy of a Cu-IUD used for 43-90 months would be just as high for a Cu-IUD used for 4 years. The life span of a Cu-IUD is limited by corrosion. The study recommends that use of a Cu-IUD with a wire surface area corresponding to 200 sq mm should not exceed 5-6 years.

Effect of various types of intrauterine foreign bodies on the incorporation of 35S into mucoprotein and of thymidine 2-14C into DNA of rat's endometrium.

PIP: The metallic ions, copper and zinc, are extensively associated with biological processes. An imbalance in the normal concentration of these metals can alter the reproductive function. The experiments reported here were done to determine whether the insertion of a metallic device into the uterus of rats is associated with metabolic changes in the endometrium. For this purpose the effect of IUDs on the incorporation of 2Na 35S40 into the mucoproteins and of thymidine 2-carbon-14 into the DNA of the endometrium of normal rats was studied. Estradiol benzoate, 20 mcg, was injected im the day before instillation with radioisotopes in order to have all the rats under similar estrogenic stimulation. In Experiment 1 either .2 mc of 2Na35S40 or 2.5 mcc of thymidine 2-carbon-14 in .1 ml of distilled water was instilled into each uterus. To avoid expulsion of the isotope a ligature was placed in the lower portion of each horn. The opposite horn served as a control. The horns were excised at different intervals from 1 to 88 hours later. The results showed that the accumulation of radioactivity in the endometrium reaches its maximum concentration in about 22 hours and then gradually declines. In Experiment 2 copper wire, zinc wire, or nylon thread was used as an IUD. The opposite horn was used as a control. About 14 days later the isotope was instilled as in Experiment 1 and left for 24 hours. In the presence of an inert foreign body, such as nylon thread, a significant decrease in the accumulation of sulfur-35 in the endometrium (18.5%; p less than .05) was noted. With zinc wire the assimulation decrese was 44.2% (p less than .001), and with copper wire, it was 69.6% (p less than .001). Absorption of thymidine 2-carbon-14 was the same in both horns in the control group. Nylon thread produced no significant difference. Copper and zinc produced statistically significant depressions of absorption (p less than .001). Copper depression was greater than zinc depression (p less than .01). The nylon thread is considered to be an inert foreign body while the copper and zinc wires are active.^ieng

Copper as a dissociating agent of liver and endometrial polysomes.

PIP: In an effort to explain the mechanism of the increased efficacy of the copper-releasing IUD, the in vitro action of copper ions on the polysome patterns of rabbit endometrium and liver was studied. The uterine horns were extracted from female rabbits with prior sexual experience. The horns were sliced longitudinally, and the endometrium carefully scraped off with a curette. For each experiment the scrapings from 4 to 6 cornua were pooled, suspended in buffer A (.14 M sucrose containing .05 M Tris-hydrochloride, .05 M potassium chloride, .005 M magnesium chloride, 200 mcg/ml heparin and brought to pH 7.6), and divided into 5 equal fractions. To 4 of the fractions, copper (as copper chloride) was added to reach final concentrations of .15, 13, 1, and 1.5 mM, respectively. The fifth fraction served as a control with no copper added. The liver was extracted, homognized in buffer A, and treated in the same way as the endometrium. The homogenates were further adjusted, treated, centrifuged, and analyzed. Results showed that the in vitro addition of copper in concentrations as low as .15 mM produced a significant decrease in the amount of polysome aggregates that could be recovered from endometrium. Liver required concentrations of at least .3 mM to show a similar effect. For concentrations of 1.5 mM copper, the recoverable amount of the polysome fraction from liver and endometrium was 40% and 25%, respectively, of that recoverable without added copper. When the obtained polysomes were analyzed in a sucrose gradient, additions of increasing concentrations of copper induced a progressived decrease of the heavy components of the polysome patterns with a concomitant increase in the lighter components. The results which show copper as a possible dissociating agent of liver polysomes are important, but it is doubtful that liver concentrations of those required to dissociate polysomes (.3 mM) will ever be reached by the use of these IUDs. It is postulated that the impairment in polysome aggregation is part of the mechanism of the copper IUD, and it may modify both the endometrial characteristics and the blastocyst viability required for successful embryo development.^ieng

Ultrastructural changes in human endometrium with copper and nonmedicated IUDs in utero.

Scanning and transmission electron microscopy were used for a study of the surface and glandular ultrastructure of human endometrium in the presence of different types of IUDs at comparable phases of the menstrual cycle. The aim of the study was to compare the effect of the nonmedicated with the copper and multiload copper devices to further explain the differences in their contraceptive potencies and their mechanism of action. The endometrium was evaluated at and away from the IUD; emphasis was put on the ultrastructure of endometrial gland openings, secretory activity, cellular glycogen content, ciliated cells, microvillous pattern, and kinocilia. The changes of the surface ultrastructure of the endometrium in the presence of copper IUDs were more extensive in this study than those previously reported. There seems to be a direct relationship between the amount of copper incorporated in the device, the degree of ultrastructure changes, and the area of endometrium involved. Copper devices affect the endometrial cells away from the IUD. The altered secretory function with disturbed macroapocrine secretion, the abnormality of ciliated cells, and the defective microvillous growth seem to interfere with the physiologic and functional integrity of the endometrium, reducing the chances of contraception in the presence of copper IUDs.

Effect of intrauterine copper on the uptake of estradiol-C 14 by rat tissues.

PIP: To study the mechanism of intrauterine copper contraceptive action, 1 uterine horn of test rats was implanted with copper wire, the other was used as control. The animals were injected with carbon-14 labelled estradiol and the concentrations in tissues were assayed. There was no difference in estradiol uptake between the 2 hours until 4 weeks postinsertion when the copper-bearing horn showed a marked increase. Upon ovariectomy, no difference in estradiol uptake was noted between the 2 horns, somewhat eliminating the possibility of missing early copper-induced increased uptake due to endogenous estradiol levels in excess amounts for saturation of receptor sites. Since the contraceptive properties of copper are manifested rapidly, the late increase in estradiol uptake suggests that primary antifertility action is not dependent upon this estrogenic effect. The histologic change of intense proliferation in the mucosal stroma in the areas of direct contact with the copper may account for the later increase in estradiol uptake.^ieng

Copper levels in women using intrauterine devices or oral contraceptives.

PIP: A study was undertaken to explore the role of the copper IUD (Cu-200) in contraception and to lower its side effects. Endometrial and plasma concentrations of copper were determined spectrographically in the late proliferative and late secretory phases in 15 women wearing the copper IUD, in 6 short-term Lippes loop users, in 23 long-term Lippes loop users, in 17 patients on oral contraception, and in 32 women who were not using contraception,y The last group of women served as controls. The findings showed a decrease in the endometrial copper level in the secretory phase but no change in the plasma concentration of copper in the control group. Both Cu-200 and Lippes loops produced a rise in endometrial copper which was significant during the secretory phase. The possibility of a local foreign body reaction is noted. Combined steroid pills caused variable degrees of increase of endometrial and plasma copper in both phases. Endometrial copper levels were elevated in both phases of the cycle, while plasma copper showed a probably significant rise in the proliferative phase only. The change in plasma copper may be explained by changes occurring in hormonal pattern during pill therapy.^ieng

Two years' experience with two levonorgestrel-releasing intrauterine devices and one copper-releasing intrauterine device: a randomized comparative performance study.

A randomized comparative performance study of two levonorgestrel intrauterine devices (IUDs) and a copper (Nova-T) IUD (Leiras, Turku, Finland) was performed at two clinics in Finland and one in Brazil. The 24-month cumulative event rates per 100 women are reported. Six thousand woman-months of use were recorded with the levonorgestrel IUD and 3000 with the Nova-T device. Pregnancy rates at 2 years of use were 0.6 and 0 with the two levonorgestrel IUDs and 3.3 with the Nova-T IUD. Removal rates because of bleeding and/or pain were low with all three IUDs: 7.5, 7.6, and 7.1, respectively, at 24 months. Recordings of the number of days of bleeding showed significantly fewer days of bleeding during use of the levonorgestrel IUDs than the Nova-T IUD from the second month of use onward, until the end of the second year. No infections were recorded in association with use of the levonorgestrel IUDs, and only one termination because of infection was recorded for the Nova-T IUD. The continuation rates of use at 24 months were 66.6, 60.7, and 71.9 for the two levonorgestrel IUDs and the Nova-T IUD, respectively; the differences were not statistically significant.

The mechanism of action of the copper intrauterine device.

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.

PIP: The mechanism of action of the copper IUD was investigated in the rabbit uteri. The effects of copper on steroid-hormone-receptor interaction and the morphologic effects of copper were studied, and the uterine copper content was measured. In vivo and in vitro results were compared. Uterine cytosol was produced by daily sc injections of 50 mcg 17beta-estradiol for 8 days into immature female rabbits. 2 days later the rabbits were decapitated and the cytosol prepared from homogenized uteri. Radioactive steroids were purchased. Radioactivity was counted with a Packard 3390 liquid scintillation spectrometer. Progesterone binding to uterine cytosol was measured. Techniques used are described. On Day 8 of priming of female immature rabbits, a copper IUD was inserted into the right uterine horn. Progesterone (1 mg) or 17beta-estradiol (50 mcg) was injected sc for another 7 days. The rabbits were decapitated on Day 8 and their uteri excised. Sections were prepared and studied histologically. Each horn was minced and homogenized. The supernatant was used as cytoplasm and the copper content of each uterine horn measured. The binding capacity of the estrogen receptor was less affected by copper than was that of the progesterone receptor. Copper was a competitive inhibitor of steroid-ho rmone-receptor binding. Results indicate that copper acts through direct interference at the steroid-binding site of the receptor resulting in the increased contraceptive effect of the copper IUD. A 5-20% sucrose linear gradient centrifugation showed that estrogen and progeste rone receptors, which both sedimented at 8S, were changed to more sedimentary forms in the presence of 10-4 M Cu ++ and were dissociated to a 6.5S form with (some loss of steroid hormone binding affinity at 10-2 Cu ++. This dissociation and aggregation of the receptor macromolecules may cause biologic inactivation of the receptors. Histological study of the uteri of rabbits bearing the copper 7 IUD showed that progestational proliferation and estrogenic activity were inhibited. The copper content of the cytoplasm was increased in the presence of a copper IUD. The greater stability of the estrogen receptor in the presence of copper suggests an increased estradiol uptake in rat uteri bearing a copper IUD. The concentration of 1.4 X 10 -6 M Cu ++ appears to be effective in the steroid-hormone-receptor interaction. However, this effect by copper cannot exclude the coexistence of some other mechanism in these phenomena.

Corrosion of filamentous intra-uterine copper. The MLCu250 and the MLCu375.

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.

Studies of duplex (copper-coated) wires for use in intrauterine 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.^ieng

Serum prolactin concentrations related to copper or inert intrauterine devices (IUDs) in women.

A report that serum prolactin concentrations were almost doubled by the use of copper IUDs led us to study the effect of both copper and inert IUDs. We studied 105 normal women in whom all other prolactinergic factors had been excluded; 25 of them were using copper IUDs, 25 were using inert IUDs and there were 55 controls. No differences were found in the mean prolactin levels between these groups (4.3, 4.5 and 4.3 microgram/l, respectively). We conclude that copper and inert IUDs do not affect prolactin secretion.

PIP: The results of a cross-sectional study designed to determine the effects of IUD material (i.e., copper or inert) on prolactin levels in serum are presented. A consecutive series of 105 healthy volunteers were studied. Prolactin was measured by radioimmunoassay. The serum prolactin determinations obtained are shown figuratively; there were no significant differences between the geometric mean values in women (n=25) with copper (4.3 mcgm/liter) or inert IUDs (n=25) (4.5 mcgm liter) or controls (4.3 mcgm); nor were differences discernable between the combined IUD groups (4.4) compared with controls (P .86 in all cases). Copper and inert IUDs do not affect prolactin secretion.

Calcareous deposits formed on IUDs in human exposures.

PIP: Characteristics of the calcareous deposits on several hundred IUDs of various designs and materials following in vivo exposures were examined, and an in vitro method of study was devised. There were 650 copper-wound IUDs and 18 plastic IUDs. The copper-wound IUDs had been in the uteri for 6-27 months; the plastic IUDs for 3 months to over 8 years. Microscopic examinations, X-ray diffraction, weight changes, and chemical analyses were used. X-ray diffraction showed that calcite (CaCO3) was the major crystalline constituent of the calcareous deposits. A large fraction of the deposited material was organic. Surfaces in contact with the uterine wall were essentially free of depos its. Microscopic inspection of copper-wound IUDs revealed the amount of deposit. Length of exposure increased the amount of deposit, but there were marked variations in amount. Accumulation of deposits was mostly at the fundal end. More marked local erosion of copper was noted where there was little or no carbonate deposit. Deposits occurred in patches on Lippes loops and Margulies spirals. The in vitro carbonate deposits did not reproduce the rates or morphology of the in vivo deposits. Variations in uterine carbonate formation are attributed to differences in uterine chemistry of individuals.^ieng

Effect of Cu2+ ions on the binding of estrogen to the human myometrial estrogen binding protein.

PIP: The effect of cupric ions on the binding of estrogen to the human myometrial estrogen binding protein was investigated. Dissociation constants at 20 degrees C for the estrogen receptor were .081, .21, and .24 mM for estradiol, estriol, and estrone, respectively. Affinity and the number of binding sites were affected in the presence of cupric ions, indicating a mixed type inhibition of the binding of steroid to receptor. The 2nd-order association rate constants decreased in the presence of cupric ions and the effect appeared to be reinforced by an increase in temperature. No change in the sedimentation coefficient of the estrogen receptor complex occurred in the presence of cupric ions although less steroid was bound. Cupric ion concentrations above 10 mcM were needed before marked alterations in the binding characteristics were established. Since the copper level in human uterine fluid of women using a copper IUD have been shown to be in the 20 mcM range, the interaction of cupric ions with the binding of estrogens to their specific receptors must be considered as 1 factor responsible for the biochemical change in the uterus which contributes to the contraceptive action of the copper IUD.^ieng

Effects of contraceptive agents on the biochemical and protein composition of human endometrium.

An analysis of the nucleic acid and protein composition of endometrial tissue was undertaken in normal women and in patients using either steroidal oral contraceptives or intrauterine contraceptive devices (IUCD). In the presence of an IUCD, endometrial RNA/DNA and protein/DNA ratios were elevated in the secretory phase of the menstrual cycle compared to values obtained in normal women. In the oral contraceptive group, endometrial RNA/DNA and protein/DNA ratios were below the normal range in the late proliferative phase of the cycle. Typical electrophoretic profiles in the oral contraceptive group were similar to the control group, although a quantitative analysis revealed that the concentrations of certain characteristic uterine proteins were reduced. In the IUCD group, there was a preferential appearance of two proteins with approximate molecular weights of 36,000 and 26,000 daltons. Another protein with a molecular weight of 48,000 daltons, which demonstrated a cyclic change during the normal menstrual cycle, was reduced in both study groups. The results suggest that both agents studied induce changes in the macromolecular composition of the human endometrium which may relate to their contraceptive effect.

PIP: Nucleic acid and protein composition of endometrial tissue taken from normal women and patients using either oral contraceptives (OCs) or IUDs was analyzed in this comparative study. Endometrial ribonucleic acid (RNA)/deoxyribonucleic acid (DNA) and protein/DNA ratios were elevated in the presence of IUDs during the secretory phase of the menstrual cycle compared to values obtained in normal women. In OC users, endometrial RNA/DNA and protein/DNA ratios were below the normal range in the late proliferative cycle phase. Electrophoretic profiles of endometria were also performed. Typical electrophoretic profiles in the OC group were similar to controls, although a quantitative analysis revealed that the concentrations of certain characteristic uterine proteins were reduced in OC users. In contrast, there was a preferential appearance of 2 proteins in the IUD group; these proteins had approximate molecular weights of 36,000 and 26,000 daltons, respectively. A 48,000-dalton protein, which demonstrated a cyclic change during the normal menstrual cycle, was reduced in both IUD and OC users. Therefore, it is concluded that both types of contraception induce changes in the macromolecular composition of human endometrium, and that these changes may be related to their contraceptive modes of action.