THE BIOLOGICAL

J.C.

Middleton,

M.Sc.(Syd.)

ACTIONS OF ENDOUTERINE COPPER

and

M.

Kennedy,

M.B.,B.S.(Syd.)

G. D. Searle International Co. Department of Clinical Pharmacology Asia/Pacific 8 West Street, North Sydney, N.S.W. Austra I ia

M.R.A.C.P.

2060

ABSTRACT

Biological activity of copper has been studied extensively over the last few years following Zipper’s observations attributing an antifertility effect to copper when placed within the uterine cavity of rats and hamsters. The antifertility effect appears to be mediated at a local rather than a systemic level and present evidence points to changes in the endometrium resulting in disruption of implantation. The spermicidal action of copper cannot be discounted as contributing to the antifertility effect at the present time. However, it would appear that copper exerts no significant effects on ovulation, fertilisation, tubal motility or embryogenesis.

Accepted

for publication

FEBRUARY

1975

December

26,

VOL. 11 NO. 2

1974

209

CONTRACEPTION

INTRODUCTION The popularity of the IUD as a method of fertility control has increased dramatically over the last decade. Improvements to the earlier devices have largely centred on changes in shape (by introduction of the bio-engineering design approach) and reduction in size. Many devices still suffer from an unacceptably high pregnancy rate, a high incidence of expulsion and menorrhagia, cramping and the problem of difficulty of insertion in the nullipara. In an effort to reduce the number of expulsions and the number of patients who could not tolerate the device, smaller devices were designed which conformed to the shape of the uterine cavity. early studies indicated that, although However, these devices were not acceptable due better tolerated by the uterus, to a high pregnancy rate (1). Davis (2) has demonstrated that the surface area of contact of an inert IUD with tho endometrium directly influences the antifertility effect. In 1969, Zipper et al.(3) reported that metallic copper exerted a potent antifertility effect within the rabbit uterus, in contrast to a stimulatory effect on ovulation when placed in other sites, e.g. hypothalamus (4) or administered as CuClz subcutaneously (5). After establishing the safety of copper in animal studies, Zipper began Th i rty mm2 of clinical trials in Chile of an IUD bearing copper wire. copper was used initially but although the pregnancy rate improved, this device still had an unacceptably high pregnancy rate (4.9 per 100 users over one year). In subsequent studies, the surface area of copper was This device reduced the pregnancy rate to 0.9 (1). increased to 120 mm’. While the mode of action of the inert IUD is not precisely known, a large number of effects have been documented and these have recently been the subject of a comprehensive review (6). The mode of action of copper IUDs would seem to be completely different to that of conventional IUDs. The main support for this hypothesis is the high pregnancy rate observed with the small devices now used as carriers for copper when copper is not added and the dramatic decrease in pregnancy rate when a small amount of copper is added to the carrier (1). The elucidation of the mode of action of copper IUDs in man is Firstly, the extrapolation of animal hampered by a number of factors. data to man is fraught with difficulties due to species variability; indeed, the effects of copper IUDs in animals are several, but the relative importance of each in different species seems to vary considerably. In addition, there are a number of biochemical variables that must It is probable that many of these parameters vary be considered. between species although few of them have been documented. Also, the active principle of copper IUDs has not yet been absolutely defined; it may be the copper itself, although this is unlikely, the cuprous ionCu+ or the cupric ion-Cut+.

210

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CONTRACEPTION

In considering the in vitro work published on the effects of copper ions, one must also bear in mind that the amount of copper released from Any experimental results obtained must be copper IUDs is small (7). correlated with the release rate observed with copper IUDs in man. Hagenfeldt (7) has shown that copper content of cervical mucus varies with the time of the cycle both before and during use of a copper IUD. In control women, the copper concentration is highest during the secretory phase but the situation is reversed when the IUD is in situ. maximal copper concentrations were With the copper device in utero, found during the proliferative phase over the first six months of use and dropped to approximately half this value during the secretory phase. it is important to take these variations into consideration when Thus, the effect of copper IUDs is being discussed in relation to different if the spermicidal effects of copper are being modes of action, e.g. considered, the values obtained during the late proliferative phase are applicable, whereas if effects on implantation are considered, midsecretory values become applicable. Such considerations do not take into account the possibility of cervical secretion of mucus containing copper, and also ignore the possibility of the dilution of uterine secretions containing high concentrations of copper by cervical secretions (8). However, if concentrations based on the Hagenfeldt data are taken as an indication of the copper concentration likely to be responsible for antifertility effects of these devices, one would expect that these would represent the Using correct order of concentration that might be expected in utero’. diluted uterine secretions, Oster (9) has shown, however, that concentrations of the order of 10-3M are attainable in vitro and it might be that such values should be considered when the uterine actions of copper are discussed. Corrosion

of

Copper

and

its

Fate

Oster (9) has shown that when copper is placed in contact with bovine serum albumin, the rate of corrosion is dependant on the area copper exposed. He considers that these results can be projected to uterine secretions and also suggests that uterine pH may be important the rate of release of copper.

of in

On a small sample, Hagenfeldt (7) found that the release rate of copper from 200 mm* copper devices is reasonably constant at 45pg/day over 430 days of use. (The f i rst 60 days were al lowed for equi I i brat ion In the uterine environment,a corrosion of the device in the uterus.) layer consisting mainly of Cu20 forms on the surface of the wire (10). Cuprous oxide would be expected to dissolve to liberate Cut. However, the balance between oxidising enzymes and reducing (sulphur-containing) and stabilising (chelating) moieties present in the uterine enzymes and secretions might be expected to determine whether cuprous ion was the or whether oxidation of Cut to the major component of released copper, cupric ion occurred rapidly.

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CONTRACEPTION

A possible reaction takes into account the copper.

sequence has been need for oxygen and

2Cu + 4H+ + O2 -

proposed by Oster pH in the corrosion

(9)

which of

ZCu++ + 2H20

In an experiment in which oxidised and reduced glutathione were the former promoted the formation of incubated with copper strips, It can be cupric ions while the latter showed little reaction. concluded from this that the disulphide bond is of critical importance in copper dissolution by acting as an oxidising agent in the formation The problem with this theoretical explanation is that while of cu++. Cuf+ can be formed by incubation with oxidised glutathione in vitro, the the major identified corrosion present evidence points to Cut as being Further work to elucidate the ionic form of copper in the compound. endometrial secretions is needed to clarify this matter. When 64Cu and 67 Cu wires are inserted into the uteri of rats, systemic absorption occurs (11). In monkeys in which intrauterine copper devices were implanted for 360 days, subsequent analysis of major *iSSueS for copper content revealed no important differences from values obtained from control animals (12). in humans with copper IUDs in situ, no change has been reported in the levels of serum copper, ceruloplasmin and ceruloplasmin oxidase activity (13). The copper released is partly removed in the uterine secret ions and part I y absorbed. Salaverry et al.(14) have studied the endometrial location of copper in humans with copper IUDs in situ, and shown that it is found in the secretory vacuole during the secretory phase but no copper is found in the endometrium during the proliferative phase. The contraceptive effect of copper IUDs will now be considered by the effects observed on ovulation, fertilisation, tubal motility, the blastocyst, the process of implantation, the endometrium, observations on protein metabolism and other secretions, and sperm. BIOLOGICAL Ovulation

and

EFFECTS OF COPPER IUDs

Fertilisation

In humans, ovulation has been shown to occur as judged by the patterns of progesterone and oestradiol in the plasma of a series of women with copper devices in situ (15). Fertilisation is not inhibited in rabbits inwhich uterine copper implants are made (16). Uterine

uterine bodies.

Motility Medel et al.(17) have observed that copper wires placed in the cavity of rabbits are less rapidly expelled than inert foreign A possible mechanism for this effect has been recently

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1975 VOL. 11 NO. 2

CONTRACEPTION

suggested by Salgo & Oster (18) who demonstrated that CUSOL, at a concentration of 10m5M caused intense contraction of the rat uterus In these experiments, in vitro and was later followed by relaxation. However, a concentration of 10m2M Cut+ was added to the bath fluid. was required to produce similar results if the CUSOI, was introduced into the lumen. Copper wire introduced into the lumen caused strong contractions after the first hour, but these decreased gradually, and sensitivity to oxytocin was also decreased. Apart from possibly increasing the retention rate of the copper IUD, this probably has little relevance to the contraceptive action. Effects

on

Implantation

and

Embryoqenesis.

Endometrial copper was first shown to inhibit implantation of rabbit blastocysts by Zipper et al.(3), and later Chang et al.(19) demonstrated similar effects on the rat and hamster. They showed that copper wire did not affect the developing blastocyst one day after This is believed to be due to an action on the implantation. endometrium and not on the blastocyst as Chang 8 Tatum (20) showed that rat blastocysts transferred from a treated to an untreated horn developed normally although it was also shown by the same authors that some blastocysts in treated horns disappeared before implantation (20). Chang & Tatum have more recently demonstrated that intrauterine copper implants caused no foetal abnormalities in groups of hamsters, rabbits and rats during pregnancies with copper in situ or in the offspring of the resulting animals (21). Brinster & Cross (22), using a culture medium containing 1 mg/ml bovine serum albumin (BSA), have demonstrated that CuClz at a concentration of 2.5 x lo-‘M is toxic to developing mouse blastocysts and causes the zona pellucida to dissolve in a protein medium in vitro. This may be interpreted as being an effect of the copper on the albumin rather than on the blastocyst itself, possibly by the disruption of S-S bonds as shown by Oster (9). This is in contrast to the observations of Whittingham (23) who showed that cupric ions at a concentration of up to 26 pg/ml (4 x 10-4M) did not have a direct toxic effect on the blastocyst when albumin was added to the incubation medium at a concentration of 4 mg/ml. He considered that protein in the uterine secretions acted as a protective medi urn. Noeslund (8) has shown that when mouse blastocysts are placed in a medium containing 3 mg/ml BSA and CuClz at a concentration similar to that found in human cervical secretion (1 x 10-4M), inhibition of zona-loss and outgrowth occurs. Jones et al.(24) incubated human adult and foetal cells in a medium containing a copper IUD and showed inhibition of growth when the culture was exposed to copper ions. It appears that CuClz has a toxic effect on blastocysts in vitro and this is a concentration-dependent phenomenon, increasing as the concentration rises. This may not apply in the in vivo situation although Noeslund (8) considers that the copper wires were removed prematurely in Chang B Tatum’s experiments.

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CONTRACEPTION

When a state of pseudo-pregnancy is induced in rats with intrauterine copper implants, the process of decidualisation is reduced in comparison to control uterine horns as judged by measurements of uterine weight (19). Endometrial

Changes

The uptake of labelled oestrogen into the endometrium of rats is increased when a copper wire is placed in the uterine cavity. Label I ed progesterone, however, is not taken up in increased amounts (25). The finding of increased oestrogen uptake has recently been confirmed by Adadevoh & Dada (26) but as this effect only occurs some weeks after insertion, it is probably only of secondary importance in the contraceptive action of copper. Oestrogenic changes have also been shown in the rabbit endometrium (3). The endometrial histology of humans with copper IUDs in situ was first reported by Zipper et al.(3) who described normal histology to light microscopy, but later reported a leukocytic infiltration of the endometrium both with copper devices and with the carrier alone (27). More extensive studies have The oestrogenic effect observed confirmed these latter results (28). in rabbits has been reported as not occurring in man (291, but in this study in which samples were taken during the proliferative and secretory there was a gradual increase phases over an 11-12 month period of time, in the number of specimens showing leukocytes in the glandular lumens, but the endometrial stroma was normal throughout the study. as great The white cell infiltration has been shown to be at least with copper IUDs as with inert plastic devices in rats (30). Cuadros & Hirsch (31) have shown that copper stimulates a much greater local exudation of polymorphonuclear leukocytes than that evoked by plastic devices and postulates a chemotactic mechanism for this observation. The present significance of this white cell infiltration is not known although it has been shown that white cells in patients with IUDs and changes in immunoglobulin levels possess phagocytic properties (321, in patients with IlJDs in situ have also been implied as being associated with this phenomenon (33). Scanning electron microscopy has demonstrated glycogen-containing apical projections in humans The significance of this finding will situ (34). Immunological

Mechanisms

Changes in the immunological briefly mentioned earlier in this globulins (IgG and IgM) have been over a period of time ranging from IUDs showed a rise in IgM but not

214

the absence of with copper IUDs in be discussed later.

status of women with IUDs have been Increased levels of immunoreview. reported in women with inert IUDs Patients with copper l-52 months. IgG after four weeks (33).

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1975 VOL. 11 NO. 2

CONTRACEPTION

it has been shown that immunoglobulin levels In studies on the rat, in the serum and uterine fluid rise dramatically after IUD insertion. The antifertility effect as indicated by the number of implantation sites is reduced by immunosupressive drugs (35). Such drugs were shown to increase the number of implants in the control horn, whereas in the an increased number of implantation sites were IUD bearing horn, detected. Effect

on

Enzymes

Although the role of the endometrial enzymes in the establishment and maintenance of pregnancy is poorly understood, the effects of copper on a number of uterine enzymes have been studied. A particular difficulty in determining the effects attributable to copper in these studies is the lack of suitable control material in the literature, i.e. studies on enzyme changes in the presence of inert IUDs. It also appears that the enzyme levels change between proliferative and secretory phases of the cycle and therefore it is necessary to consider the implications of a change in activity in either phase with regard to the proposed mode of action. Thus, the importance of glycogen levels and enzyme activity related to glycogen metabolism would seem to be more important during the late secretory phase. Enzymes which have been studied in both conventional and copper IUD users include alkaline phosphatase (36,37), cytochrome C oxidase (38) and catalase (39). Glycogen levels have also been studied with both devices (37,391. Changes induced by inert and copper-containing the endometrium and the uterine fluid are summarised significance of these studies will be discussed for groups stud ied. (a)

Enzymes

containing

or

inhibited

IUDs on enzymes of in the Table. The the various enzyme

by copper

With conventional IUDs, the effects on these enzymes (catalase, peroxidase and cytochrome C oxidase) were variable whereas the activity of two of the three enzymes studied increased in the presence of copper. Dasgupta et al.(38) have suggested that the marked increase in catalase activity and consequent more rapid removal of toxic end products may be responsible for the reduced As cytochrome C incidence of side effects with copper IUDs. oxidase is involved in cell respiration, an increase in the activity of this enzyme would not be expected to play a part in the contraceptive action of copper devices. (b)

Zinc-containing

enzymes

The activity of the zinc-containing enzymes lactic dehydrogenase and alkaline phosphatase) studies employing copper in spite of constant protein although the change in LDH activity reach significance (see the Table). It has copper may displace zinc from these enzymes ponding decrease in activity (1).

FEBRUARY

1975 VOL. 11 NO. 2

(carbonic anhydrase, decreases in all increases in total observed (37) did not been suggested that and cause a corres-

215

CONTRACEPTION

TABLE Studies

of

the

effects

of

intrauterine

devices

Conventional

uterine

IUD

P**

ENDOMETRIAL ENZYMES

on

enzymes

Copper

s

IUD S

P**

Catalase

4

(38)t

4

(38l.t

Perox i dase

4

(38)t

0

(38)-t

+

(38)t

+

(38)t

4

( 36

Cytochrome Alkaline

C Oxidase Phosphatase

)

++

+

(9) + (37) + (40) J (37)

0

$ (37)

0 0

Acid

c

Phosphatase

(36)

B-Glucuronidase Lactic

Dehydrogenase

Carbonic

0 (37)

++

Anhydrase

(9)

4”

Glycogen-endometrial

f”(42)

Amy I ase

+ (41)

Glycogen

synthetase

+ (41)

Phosphory

I ase

0

(41)

t

(37)

Protein UTERINE Prote

FLUID

ENZYMES

in

Acid

phosphatase

Alkaline

phosphatase

4

+(36)

0

o(39)

f

f(39)

0 (54)

G

)(39)

0

o(39)

Lactic

Dehydrogenase

Glucose-6-phosphatase

0

o(39)

Glucose-6-phosphate dehydrogenase

0

o(39)

Uter

+

t(39)

ne fluid-glycogen

*Long

term

‘Commercial tAs 4

216

enzymes

compared

Increased Numbers

**P

l+

in

with

= proliferative Not

used. intact

iDecreased parentheses

refer

phase inhibited

controls.

0 (54)

4

0

0 (54)

B-Glucuronidase

Hyaluronidase

0

by

S = secretory incub”

with

(54)

phase

Cu

See discussion o = no change

to

reference

in

text

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CONTRACEPTION

It is notable that the decreased activity of endometrial alkaline phosphatase in the secretory phase parallel led the decrease in zinc concentration, while the LDH activity decreased only slightly in the secretory phase (37). The fall in endometrial alkaline phosphatase activity may well be more marked than the assay indicates as this fall occurs despite the infiltration of leukocytes which are known to be rich in this enzyme. However, Oster (91, in demonstrating the inhibition of carbonic anhydrase and alkaline phosphatase activity in vitro, suggests that this is due to reduction of disulphide groups in the enzymes and inactivation of these enzymes, points out that Cut+ did not cause as might be expected if the mechanism is via exchange of Cu++ for Zn++. However, Wilson (40) points out that alkaline phosphatase derived from human intestine differs in kinetic and electrophoretic properties from the endometrial enzyme and similar differences might be expected with the calf intestinal enzyme used by Oster In Wilson’s experiments, copper caused inhibition of the (9). enzyme in the secretory phase, while cupric ions, at concentrations which might be expected in utero, inhibited the activity of the endometrial alkaline phosphatase in both phases of the cycle (40). Alkaline phosphatase activity has been shown to increase dramatically in the early secretory phase in conventional users (36) and this suggests that copper IUDs might have mechanism of action independent of leukocyte accumulation.

IUD a

(c)

Lysosoma I enzymes - acid phosphatase and B-glucuronidase. These two enzymes differ in their response to copper (371, and in view of the fact that leukocytes are rich in both enzymes, this suggests that the effect of copper on the lysosomal enzymes Further studies may clarify these results. may be quite complex.

(d)

Enzymes

concerned

with

qlucose

metabolism

The activity of amylase is decreased in the presence of a copper device (41) but the activity of glycogen synthetase, although varying over the cycle, did not change significantly from that observed during control periods, at least in the short term, as these studies only extended over three cycles post-insertion. These authors did note that the gradual rise in glycogen synthetase activity over the cycle was not observed when a copper device was in utero. de la Osa et al.(42) found that although However, the alvcoaen content of the endometrium did not increase significantly during the first four cycles with a copper device in utero, such an increase was noted after more than five It has been suggested (34! that secretion of cycles of use. carbohydrates by the secretory endometrium might be impaired in the presence of a copper IUD as electron microscopic studies have

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217

CONTRACEPTION

revealed a decrease in the number of apical protrusions on the endometrial surface. Whether or not the decrease in the number of protrusions is a result of decreased glycogen synthesis has not yet been determined. Decreased amylase activity (41) would, in any case, be expected to decrease the available carbohydrates in the uterine secretion and this might result in deprivation of the blastocyst of nutrients prior to implantation. Protein

and

Nucleic

Acid

Synthesis

Prager (43) has shown that the incorporation of C14-labelled thymidine into rat endometrial DNA is inhibited by the presence of copper and also by zinc - another element shown to have contraceptive properties. However, Hagenfeldt (37) claims that changes in endometrial DNA or RNA concentrations are found in copper IUD users. This is in contrast to studies on inert IUDs (36) where has been shown to increase in the endometrium.

no RNA

In addition to her work on DNA, Prager (43) has demonstrated that copper decreases the assimilation of radio-label led sulphate into mucoproteins to a much greater extent than an inert IUD and suggests that depression of mucoprotein synthesis may possibly contribute to the Recently, Hernandez et al.(44) contraceptive actions of copper IUDs. have shown in vitro that cupric ions produce a decrease in the amount of polysome particles in the endometrium at concentrations which do not produce a significant change in the polysome content of the liver. As polysomes are intimately involved in protein biosynthesis, it has been postulated that copper IUDs may owe at least part of their activity to this mechanism. However, the copper concentration required to produce a decrease is somewhat lower than the endometrial Salaverry et al.(14) concentration found in women using copper IUDs. have shown that copper is selectively concentrated in the secretory vacuole of epithelial cells. Effects

on the

Sperm

Although conventional IUDs have been shown to have no effect on sperm mobility (45), they have been shown to produce accumulations of macrophages and giant cells which are known to phagocytose sperm (32). Davis (2) infers that the degree of change of the uterine milieu is directly related to the area of interaction between the device and the As the currently used copper IUDs are small in endometrium. comparison to the conventional IUDs,it is unlikely that this mechanism would play a significant part in their mode of action.

(46). sperm wire.

218

The adverse effects of copper on sperm have been known since 1850 Recently, Ullman 8 Hammerstein (47) demonstrated inhibition of motility in a preparation containing cervical mucus and copper

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1975 VOL. 11 NO. 2

CONTRACEPTION

Hagenfeldt (7) has carried out extensive studies on the effects of copper IUDs on the trace element content of the uterus and its of twelve months in which the device was env i ronment . Over a period in situ, the copper content of the endometrium increased considerablv over the first 2-3 cycles but then dropped off to values The copper concentration in cervical mucus increased close to controls. significantly in the proliferative phase but this tended to drop off although it still remained at a towards the end of the year, During the concentration some three times that of the control samples. secretory phase, the copper concentration was still increased, but the The copper increase was only marginally higher than control values. concentration during the first half year in situ was approximately This was the maximum concentration at any time during the 3.3 x !O-5M. Therefore,any consideration of possible spermicidal effects of study. IUDs must take this normal expected copper concentration into account. In 1955 White (48) investigated the effects of a number of metal ions on sperm and found that copper was toxic to human sperm at a Wide variation was observed between concentration of 2.0 x 10s3M. Incubation of copper wires in cervical mucus species in this study. causes inhibition of the migration of sperm within 60 minutes and the sperm are immobilised within 240 minutes (49). Jecht 8 Bernstein (50) have found that copper sulphate is a less potent inhibitor of sperm motility than is metallic copper incubated in seminal plasma or serum and this may add further weight to the argument that Cut is the active There is only one report of the effects of Cut (CuCI) on sperm species. sperm motility very rapidly (5 minutes), the (51). While Cut inhibited concentration used (8 x 10-2M) does not permit extrapolation to the Other investigators have determined the situation with the co per IUDs. effects of CuSOq (lo- g -10m4M11) on sperm motility. At concentrations as low as 2 x 10s4M, Saito et al.(52) found copper markedly inhibited sperm motilit and motility was still depressed at copper concentrations of 2 x IO- z M. Effects

does

on Subsequent

Fertility

Medel et al.(53) have not affect subsequent

demonstrated fertility in

that rats

endometrial after one

copper month in

wire situ.

CONCLUS IONS The addition of copper to plastic IUDs results in a dramatic increase in the effectiveness of the device as a contraceptive agent. While the active moiety has not yet been absolutely defined, it has been established that a 200 mm2 device releases between 25 and 45 micrograms of copper per day in man after equilibration within the uterus. It has been suggested that copper ions complex with disulphide groups in protein and this is important in the dissolution of copper in utero.

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CONTRACEPTION

it is copper

the

Intrauterine copper does not affect ovulation or fertilisation unlikely that changes in uterine and tubal motility induced contribute to its mode of action as a contraceptive.

Present blastocyst

evidence is insufficient at concentrations that

to substantiate occur in utero.

a toxic

and by

effect

on

Morphological changes in the endometrium which have been reported include an absence of glycogen-containing apical projections and a leukocytic infiltration. However, this latter observation has not been confirmed by all investigators and in those studies in which such an infiltration was reported, it was considered to be less than that observed with inert IUDs. Increased levels of immunoglobulins have been reported after short-term use of copper IUDs, but it seems possible that changes in the immunoglobulin levels are different to those reported with inert IUDs. Significant changes in endometrial levels of some enzymes have been noted in women using copper IUDs. The activity of zinc-containing enzymes decreases in all studies employing copper and this decrease parallels the decrease in endometrial zinc concentration which occurs with the copper IUD in situ. Some of these enzymes such as alkaline phosphatase have been considered important in the nutrition of the developing embryo. Lysosomal and copper dependenf enzymes vary in their response to copper and while glycogen concentration increases, alphaamylase concentration decreases with a copper device in utero. Copper has been shown to cause a decrease in the incorporation of labelled thymidine into rat endometrial DNA and this may reflect a general decrease in nucleic acid synthesis. Such inhibition would be expected to explain the decreased protein synthesis which has also been described. Cut+ has been shown to be toxic to sperm in a number of studies, but there is probably little correlation with copper levels observed when incubated in cervical mucus, utero and it appears that copper, provides a more potent spermicidal effect.

in -

It can be concluded from studies published over the last few years that the mode of action of copper IUDs is primarily associated with the disruption of the process of implantation although at the present time, a possible spermicidal effect cannot be excluded as a contributing factor. Acknow

I edgement

We wish to thank Miss A. assistance in the preparation

220

Appleby of this

and Mrs. J. manuscript.

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1975

for

secretarial

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Zipper, J., Human fertility antagonisms Publication

Tatum, H.J., Medel, control through of trace elements. HR.DFR/68.7, 1968,

2.

Davis, H.J. and future

3.

Zipper, J.A., Tatum, H.J., Pastene L., Medel, M. and Rivera, Metallic copper as an intrauterine contraceptive adjunct to “T” dev i ce. Amer. J. Obstet. Gynec. 105:1274-1278 (1969).

4.

Suzuki, M. and Hiroi, M. Mechanism of Sixth pregnancy in the rabbit and rat. Tel Aviv, 199 (1968).

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Noeslund, G. Contraception

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Corrosion phenomena on copperJohnson, A.B. and Maness, R.F. wound IUDs exposed in human subjects. Batelle Population Study Center Program. Apri I 1972. Submitted to G. D. Searle & Co.

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Intrauterine prospects.

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G.K. Ster.

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M., Pastene, L. and Rivera, M. the use of endouterine metal WHO Scientific Group Geneva, Switzerland.

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Scheinberg, I.H. Science 177:358-360

Tatum, H.J., Brinson, A.O. and Hood, W. tissues of Rhesus monkeys bearing intrauterine Fert. Ster. 24:848-853 (1973). copper devices.

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CONTRACEPTION

14.

Salaverry, G., Mendez, M. del C., Zipper, J. and Medel, M. Copper determination and localization in different morphologic components of human endometrium during the menstrual cycle in copper intrauterine contraceptive device wearers. Amer. J. Obstet. Gynec. 115:163-168 (1973).

15.

K. and Johansson, E.D.B. Nygren, bleeding during ovulatory cycles contraceptive device. Amer. J.

Premature onset of menstrual in women with an intrauterine Obstet. Gynec. 117:971-975 (1973).

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Polidoro, to inhibit 23:151-154

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Medel, M., Espinoza, C., Zipper, J. and Prager, observations on the effects of copper, zinc and I.U.F.Bs on the uterine motility of the rabbit. Contraception 5:203-213 (1972).

18.

Salgo, M.P. and Oster, Fert. the rat uterus.

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Tatum, H.J. and Kincl, F.A. The effect Chang, C.C., uterine copper and other metals on implantation in Fert. Ster. 21:274-278 (1970). hamsters.

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Chang, C.C. and of intrauterine

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Chang, C.C. intrauterine Contraception

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Brinster, implantation

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THE BIOLOGICAL J.C. Middleton, M.Sc.(Syd.) ACTIONS OF ENDOUTERINE COPPER and M. Kennedy, M.B.,B.S.(Syd.) G. D. Searle International Co. Depar...
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