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Studies of the physiological activity of IUDs containing copper
STUDIES OF THE PHYSIOLOGICAL ACTIVITY OF IUDs CONTAINING COPPER
J. Zipper, M. Medel, L. Pastene, L. Torres, A. Osorio, M. Rivera, and C. Toscanini Department
of Physiology and Biophysics University of Chile School of Medicine Casilla 6524 Santiago, Chile
ABSTRACT The pharmacological properties of two associated metals, Cu-Zn and Cu-Ag, placed in the uterine cavity on plastic IUDs were studied to determine their contraceptive effectiveness and their capacity to modify uterine contractions. It was found that the association of Cu and Zn as pure metals results in a high degree of contraceptive effectiveness. The association of Cu-Ag causes a higher pregnancy rate than when the vector carries Cu alone, as Ag apparently depotentiates the contraceptive action of Cu. The use of a Cu-Zn alloy causes complex problems in quantifying the dissolution of these metals in the uterine cavity.
Accepted
JULY 1975
for p u b l i c a t i o n March 4, 1975
VOL. 12 NO. 1
1
CONTRACEPTION
INTRODUCTION The theoretic bases for the use of metals as endouterine contraceptives have been extensively discussed by us (1,2) and other authors in different studies (3,4). The most important physiological alterations produced by endouterine metals have reference to endometrial, spermatic and myometrial physiology. For the myometrium, uterine motility is modified in the presence of Cu and Zn (5,6) cations, those cations which have been most studied. There is a large amount of experience with endouterine Cu (7-9); and the Cu-7 200 and TCu 200 devices are now inserted on a routine clinical basis.
Our i n i t i a l s t u d i e s i n r a b b i t s d e m o n s t r a t e d t h a t b o t h Cu as w e l l as Zn, p l a c e d i n t h e e n d o u t e r i n e c a v i t y , h a v e c o n t r a ceptive properties. These metals altered uterine motility in t h e r a b b i t and r a t ( 5 , 6 ) and m o d i f i e d t h e e n d o c r i n e p h y s i o l o g y of the endometrium of the rat (i0). The studies of Chang et al. (3) with different metals confirmed the concept that Cu an~--Z~are the most potent contraceptives of all the mtals studied. The principal mechansims for their contraceptive activity appear to be located at the endometrial level (9). The effect of metallic cations in vitro on spermatic physiology has been demonstrated by varlous authors (11). In vivo studies also indicated that this mechanism is involve-H--~f~. The potentiation of the antispermatic effect in vitro by the associated metallic pairs of Cu-Ag, Cu-Zn and Cu-Ni has. been investigated by Kesseru and Leon (13). The concept of potentiation of the contraceptive properties of Cu by other metals was initially studied in this laboratory (2). An association of 30 mm 2 of Cu with 47 mm 2 of Zn on a plastic shaped vector was used. IUDs with these two metals offered complete contraceptive effectiveness in the first year of use (9). The first pregnancies appeared in the 15th ordinal month when there was no Zn left on the device due to the high solubility of the metal in this medium. The clinical experiments were prematurely discontinued when the endome~rial biopsies suggested the presence of irregular histologic findings (2) in some users, and also due to the fact that an optimal Cu contraceptive device was in its first phases of development. Actually, some of the limitations of endouterine copper as a contraceptive are known (1,4), e.g., even with larger surfaces than 300 mm 2 of Cu, both on the Cu 7 (14) as well as on the T device (4), a clinical 0 pregnancy rate has not been obtained. Nevertheless, rates of 1 or less per 100 women years have been obtained, particularly in nulligravid women (15). The Cu-7 200 and TCu 200 devices are contraceptives especially indicated for nulliparous women (16). Clinically,
2
JULY 1975
VOL. 12 NO. 1
CONTRACEPTION
their use effectiveness is comparable to that of oral steroids (17). Their effectiveness in multiparous women may be superior to any inert device yet investigated [18). The recent publication of Kesseru et al. (19) containing the enhancement of the contraceptive e f f ~ e n e s s of an Aries copper IUD with Cu-Ni and Cu-Ag combination, togethe~ with the initiation of an intense research by the Battelle group (20) of the device called the Anderson Leaf, a silicone rubber sheath impregnated with Cu and Zn powder, prompt ed us to present our results of studies with Zn and Ag associated with Cu and the effectiveness of a Zn-Cu alloy. The aim of associating other metals specifically to copper is to improve the clinical results of the best active metallic device in actual use. The desired improvements are: (a) to increase the contraceptive activity by reducing the pregnancy rate to 0, as with the Cu-7 and TCu devices, the pregnancy rate is approximately 0.9 to 2 per 100 women years in the first year of use (15); (b) to decrease the expulsion rates using biochemical and not mechanical retention, that is, using the depressing effects of some metals upon myometrial activity and developing the self-retention concept; (c) to minimize the secondary effects such as excessive bleeding and pain; (d) to maintain the effectiveness of these parameters for no less than 3-5 years; and (e) to demonstrate clinical safety such as was shown with endouterine Cu. Apparently the associated metals which could fulfill some of these aims are combinations of.Cu-Ag and Cu-Zn. Our experience with these metal associations on two plastic vectors that have been extensively studied with copper alone, the T and 7 devices, are presented here. MATERIAL AND METHODS The 7 vector, already extensively described in other publications (9), was used as a carrier. Group 1: A wire alloy of 80% Cu and 20% Zn (100 nun2) were added to its vertical arm. Group 2: adding 40 mm 2 of Ag to the Cu-7 200 devices, as a 0.2 mm diameter wire wound around the superior portion of the vertical arm. Group 3: adding 47 mm 2 of Zn, as a wire of 0.5 mm diameter, wound around the superior portion of the vertical arm of the Cu-7 200 device (Figure I). The T vector, already fully described in other publications (2), was u s e d as a carrier. Group 4: adding to the suver~or portion of the vertical arm, 30 mm 2 of Cu and 47 nun z of Zn as an 0.5 nun diameter wire. Group 5: the same material wire as group 4 only on the inferior portion of the vertical arm. Group 6: in the superior portion of the vertical arm, a wire 0.5 mm in diameter of 47 mm 2 of pure Zn was added (Figure 2).
JULY 1975
VOL. 12 NO. 1
3
CONTRACEPTION
£.=_._~ --
C)
Figure I. ?- to =
31
7Cu-Zn 100mm 2 (alloy)
Figure
33
3~
Cu7 200 Zn 47mm 2
2.
T Zn
47mm 2
uterine
4
Cu7 200 Ag 4 0 m m 2
3'2
C)
fundus
TCu 30mm2-Zn 47mm 2
TCu 30mmm-zn 47mm 2
uterine
uterine
segment
JULY 1975
fundus
VOL. 12 NO. 1
CONTRACEPTION
The patients enrolled in this study were essentially multiparous and the insertions were performed after a menstrual period. The number of patients included in each group was: Group 1 = 492; Group 2 = 449; Group 5 = 243; Group 4 = 311; Group 5 = 214; and Group 6 = 191. All the groups with the exception of Group 6 were analyzed by the life table method. The exception was not qualified for precise analysis as the patients in this group had less than 6 months of exposure. Endometrial biopsies with stained hematoxylin-eosine were performed in all the groups in different periods of the cycle and with different periods of exposure, all less than one year. The results of groups 4, 5 and 6 have been descirbed in a previot publication (2). In group I, 50 endometrial biopsies were performed; in group 2, 45 biopsies and in group 3, 46 biopsies were performed.
RESULTS The results are summarized in Tables I and II~ The clinical experiments performed with the T vector demonstrate that the Cu-Zn association (30 m ~ C u and 47 mmZZn) localized in the uterir fundus reduced the pregnancy rate to 0 in the first year of use. Pregnancies occurred when the Zn had completely dissolved (the first pregnancy occurred in the ISth ordinal month). When this component is localized in the inferior segment of the vector, the pregnancy rate is 4.8. The statistical analysis was performe according to Tietze and Lewit (21). The clinical experiments performed with the 7 vector indicat that: a) the addition of 40 mm 2 of Ag to the Cu-7 200 device apparently antagonizes its contraceptive effectiveness without improving any of the other important clinical parameters significantly (Table If); b) a Cu-Zn alloy, I00 mm 2 in surface area, does not significantly reduce the pregnancy rate in the first year (Table If); and c) sufficient experience has not been accumulated with the combination of Cu-7 200 plus 47 m ~ of Zn to determine its total effectiveness, but the preliminary results indicate a definite reduction of pregnancies in this group. Due to the histological alterations found in the users of TCu 30 mm2,Zn 47 m ~ and TZn 47 m ~ devices described in a previous publication (2), special care was taken when observing the histological patterns presented in groups 1 and 3. Of the 96 biopsies performed in this group, no pathological alterations were observed, but some functional modifications were found; of the 40 biopsies performed in the secretory period, II of them were characterized by a late secretory maturation in comparison with the day of the cycle. Nevertheless, these observations must be considered preliminary, as the patients have less than one year of use.
JULY 1975
VOL. 12 NO. 1
5
CONTRACEPTION
TABLE I CUMMULATIVE
RATES OF EVENTS AND CLOSURES PER i00 USERS
BY TYPE OF TERMINATION T-CuZn
(UTERINE FUNDUS),
T-Zn
FOR THE DEVICES
T-CuZn
(UTERINE FUNDUS)(Cu
(UTERINE SEGMENT),
30 mm 2 Zn 47 mm 2)
ONE YEAR OF USE
T-CuZn ~-~ne fundus)
T-CuZn ~6t-~ne segment)
T-Zn -~u-~rine fundus)
0.0±i.i(*)
4.8±2.9(*)
3.1±2.7(*)
3.1±2.0(*) 0.3
1.4±1.6(*) 0.5
1.8±2.0(*) 0.0
2.4 0.3 2.0 2.7 0.3 1.8
2.3 I.I 2.2 5.1 0.0 4.7
1.6 1.2 5.0 2.4 0.6 4.1
0.0
4.8
3.1
1.7 0.3
0.0 0.5
1.2 0.0
1.7 0.3 2.0 2.4 0.3
1.9 I.I 2.2 5.1 2.1
1.6 1.2 4.5 2.4 0.6
rents
Pregnancies Expulsions First Later Removals Bleeding Pain PID Other medical Personal relevant Planning pregnancy Relevant closures
Pregnancy Expulsions First Later Removals Bleeding Pain PID Other medical Personal relevant Continuation
rate
Women months
of use
Initial
insertions
91.3
82.3
5,165.5
1,298.5
511
214
1,829.5 191
t)
Exact calculation
t)
This value is low due to removals at investigator's choice because of high risk of pregnancy
6
for 95% confidence
85.4 (**)
interval
JULY 1975
VOL. 12 NO. 1
CONTRACEPTION
TABLE II CUMULATIVE RATES OF EVENTS AND CLOSURES PER I00 USERS BY TYPE OF TERMINATION FOR THE DEVICES Cu7-200 Ag 40mm 2, 12 MONTHS OF USE Cu7 Zn 100mm2(alloy 80% Cu ~ 20% Zn) ll MONTHS OF USE
Cu7 200 Ag 40mm m Cu7 Zn 100mm 2 12 months Alloy 80% Cu 20% Zn II months Events Pregnancies Expulsions First Later Removals Bleeding Pain PID Personal relevant Planning pregnancy Investigator's choice
5.0_+2.2*
3.1+1.6"
7.7_+2.6* 1.6
5.5±2. i* 0.7
2.2 1.5 0.7 i.O 3.0 0.2
0.8 0.8 0.2 0.0 2.3 0.6
S.O
3.1
3.8 1.3
1. o.
2.2 1.s 0.7 1.0 0.0 0.2
0 0 0 0 0 0
Revevant closures Pregnancy Expulsions First Later Removals Bleeding Pain PID Personal relevant Other medical Investigator's choice Total closures
IS .7
7.
Continuation rate
84 .3
92.
4 , 2 S I ,0
2,776.
Women months of use Number of insertions
449
492
*95% confidence limits
J U L Y 1975
V O L . 12 N O . 1
7
CONTRACEPTION
DISCUSSION The experiments we have performed up to now indicate that the association of certain metals, such as Cu and Ag do not potentiate the contraceptive action of Cu, as the rates of pregnancy on a 7 vector were increased from about 2 to 5 in the first year of use. Kesseru et al.(19) reported a 0 pregnancy rate with a Cu-Ag IUD with l~6--~tients, with 1,306 months of exposure. A plastic vector names Aries, which was used in their study, when used with no active component had a relatively high rate of contraceptive activity, 4.4 in comparison with the plastic T alone. The 0 pregnancy rate found in the above study is probably due to the insufficient months of observation. Vectors of large surface areas such as the Aries or Loop D cannot be used to demonstrate potentiation of contraceptive activity with metals due to the fact that the high leucocytic mobilization produced by the vector alone probably overcomes any action of the cations in the uterine milieu, without resulting in an improvement of the effectiveness of the metal carrying IUDs [7). The alloy, Cu 80% and Zn 20%, with i00 m m 2 surface area did not significantly increase the contraceptive rate of an equivalent surface of Cu alone. This finding might be due to the fact that the solubility of an alloy in the uterine milieu could be extremely low and impossible to.predict in an in vitro experiment, as the quantitative release of each of these cations is unknown. Many different combinations must be tried in vivo before the optimal proportion of the alloy can be achiev-'6~. The combination that presents the most potential is the association of 2 pure metals, Cu and Zn, with which a 0 pregnancy rate was obtained when they are localized near the uterine fundus. The exact quantification and precise optimal localization in the uterine cavity of each of these metals requires further study. The other factors to be intensely investigated are the demonstration of the safety of endouterine Zn and the quantification of other secondary effects that lead to discontinuation of the method, such as excess bleeding and pain. Furthermore, in order to determine whether the clinical effects noted with this Cu-Zn combination are actually due to effects of the metal and not optimal placement of the IUD, randomized comparative clinical trials with this device and pure C u b e a r i n g IUDs needs to be performed.
8
JULY 1975 VOL. 12 NO. 1
CONTRACEPTION
CONCLUSIONS I.
The only pure metals that could produce a 0 pregnancy rate in our experience are a combination of Cu and Zn placed near the fundus of the uterus.
2.
The use of Zn and Cu alloys ~resents complex problems of dissolution in the uterine mllieu that require further investigation. REFERENCES
i.
Zipper, J., Medel, M. and Prager, R.: Suppression tility by intrauterine copper and zinc in rabbits. Obstet. Gynec. 105:529, 1969.
Z.
Zipper, J.,Tatum, H.J., Medel, M., Pastene, L and Rivera, M.: Human fertility control through the use of endouterine metal antagonists of trace elements (EMATE). Fifteenth Nobel Symposium on Control of Human Fertility, 199, 1970.
3.
Chang, C.C.,Tatum, H.J. and Kincl, F.A.: The effect of intrauterine copper and other metals on implantation in rats and hamsters. Pertil. Steril. 21:274, 1970.
4.
Tatum, H.J.: Copper-bearing Obstet. Gynec. 17:95, 1974.
5.
Medel, M., Espinoza, C. and Zipper, J.: Preliminary observation on the effects of copper, zinc and polyethylene IUFB on the uterine motility of the rabbit. Contraception 5:205, 1974.
6.
Salgo, M.P. and Oster, G.: hibition of the rat uterus.
7.
Lippes, J., Zielezny, M., Ferro, P. and Sultz, H.: The effect of increasing copper on Loop A and comparisons with the copper T-200 and Loop D-plain. IUD Workshop, Battelle, October 18-20, 1975, Seattle, Washington.
8.
Stewart, W.C., Gibor, Y., Deysach, L. and Nissen, C.: Clinical studies with the Cu 7: A comparison of results in parous and nulliparous women. Clinical Proceedings of the International Planned Parenthood Federation. SouthEast Asia and Oceania Regional Medical and Scientific Congress, Sydney, 14-18 August, 1972. Published by the Australian and New Zealand Journal of Obstetrics and Gynecology.
JULY 1975
VOL. 12 NO. 1
intrauterine
devices.
of ferAm. J.
Clin.
Copper stimulation and inPertil. Steril. 25:113, 1974.
9
CONTRACEPTION
Z i p p e r , J . , Medel, M., S e g u r a , R. and T o r r e s , L . : Biological action of copper. Development o f a new t y p e o f intrauterine contraception Cu 7. Clinical Proceedings IPPF. South-East Asia and Oceanic Congress, pp. 193, 1972. Australian and New Zealand Journal of Obstetrics and Gynecology. Aedo, A.R. and Zipper, J.: Effect of copper intrauterine devices (IUDs) of estrogen and progesterone uptake by the rat uterus. Fertil. Steril. 24:345, 1973. Kesseru, E. and Camacho-Ortega, P.: Influence of metals on in vitro sperm migration in the human cervical mucus. Contraception 6:231, 1973. Croxatto, H.B., Faundes, A. and Medel, M.: Studies on sperm migration in the human female genital tract. Colloques IN$ERM 26, 1973. Kesseru, E. and Leon, F.: Effect of different solid metals and metallic pairs on human sperm motility. Int. J. Fertil., in press. Zipper, J. and Medel, M.: Factors that limit the efficiency of copper-carrying IUDs. IUD Workshop, Battelle, October 18-20, 1973, Seattle, Washington, In press. Steward, W.C.: The copper 7 device. Presented at the VI Reunion de la Asociacion Latinoamericana de Investigaciones en Reproduccion Humana, Lima, Peru, August 25-28, 1974. 6
Copper IUD protects never-pregnant, gest 3:11, 1974.
7.
Mishell, D.R., Jr., Israel, R. and Freid, N.: A study of the copper T intrauterine contraceptive device (TCu 200) in nulliparous women. Am. J. Obstet. Gynec. 116:1092, 1973.
8.
Orlans, B.: Intrauterine devices, performance to date. Population Report, I. December, 1973.
9.
Kesseru, E., Hurtado, H. and Mehe, B.: Copper IUD: Enhancement of its efficacy by addition of silver and nickel. Contraception 9:141, 1974.
0.
Development of improved IUDs. Battelle, Seattle, Washington, Seventh Progress Report, July 1973-January 1974.
i.
Tietze, C. and Lewitt, S.: Recommended procedures for the statistical evaluation o f intrauterine contraception. Studies in Family Planning 4:35, 1973.
10
in Family Planning Di-
JULY 1975
VOL. 12 NO. 1
J. Zipper, M. Medel, L. Pastene, L. Torres, A. Osorio, M. Rivera, and C. Toscanini Department
of Physiology and Biophysics University of Chile School of Medicine Casilla 6524 Santiago, Chile
ABSTRACT The pharmacological properties of two associated metals, Cu-Zn and Cu-Ag, placed in the uterine cavity on plastic IUDs were studied to determine their contraceptive effectiveness and their capacity to modify uterine contractions. It was found that the association of Cu and Zn as pure metals results in a high degree of contraceptive effectiveness. The association of Cu-Ag causes a higher pregnancy rate than when the vector carries Cu alone, as Ag apparently depotentiates the contraceptive action of Cu. The use of a Cu-Zn alloy causes complex problems in quantifying the dissolution of these metals in the uterine cavity.
Accepted
JULY 1975
for p u b l i c a t i o n March 4, 1975
VOL. 12 NO. 1
1
CONTRACEPTION
INTRODUCTION The theoretic bases for the use of metals as endouterine contraceptives have been extensively discussed by us (1,2) and other authors in different studies (3,4). The most important physiological alterations produced by endouterine metals have reference to endometrial, spermatic and myometrial physiology. For the myometrium, uterine motility is modified in the presence of Cu and Zn (5,6) cations, those cations which have been most studied. There is a large amount of experience with endouterine Cu (7-9); and the Cu-7 200 and TCu 200 devices are now inserted on a routine clinical basis.
Our i n i t i a l s t u d i e s i n r a b b i t s d e m o n s t r a t e d t h a t b o t h Cu as w e l l as Zn, p l a c e d i n t h e e n d o u t e r i n e c a v i t y , h a v e c o n t r a ceptive properties. These metals altered uterine motility in t h e r a b b i t and r a t ( 5 , 6 ) and m o d i f i e d t h e e n d o c r i n e p h y s i o l o g y of the endometrium of the rat (i0). The studies of Chang et al. (3) with different metals confirmed the concept that Cu an~--Z~are the most potent contraceptives of all the mtals studied. The principal mechansims for their contraceptive activity appear to be located at the endometrial level (9). The effect of metallic cations in vitro on spermatic physiology has been demonstrated by varlous authors (11). In vivo studies also indicated that this mechanism is involve-H--~f~. The potentiation of the antispermatic effect in vitro by the associated metallic pairs of Cu-Ag, Cu-Zn and Cu-Ni has. been investigated by Kesseru and Leon (13). The concept of potentiation of the contraceptive properties of Cu by other metals was initially studied in this laboratory (2). An association of 30 mm 2 of Cu with 47 mm 2 of Zn on a plastic shaped vector was used. IUDs with these two metals offered complete contraceptive effectiveness in the first year of use (9). The first pregnancies appeared in the 15th ordinal month when there was no Zn left on the device due to the high solubility of the metal in this medium. The clinical experiments were prematurely discontinued when the endome~rial biopsies suggested the presence of irregular histologic findings (2) in some users, and also due to the fact that an optimal Cu contraceptive device was in its first phases of development. Actually, some of the limitations of endouterine copper as a contraceptive are known (1,4), e.g., even with larger surfaces than 300 mm 2 of Cu, both on the Cu 7 (14) as well as on the T device (4), a clinical 0 pregnancy rate has not been obtained. Nevertheless, rates of 1 or less per 100 women years have been obtained, particularly in nulligravid women (15). The Cu-7 200 and TCu 200 devices are contraceptives especially indicated for nulliparous women (16). Clinically,
2
JULY 1975
VOL. 12 NO. 1
CONTRACEPTION
their use effectiveness is comparable to that of oral steroids (17). Their effectiveness in multiparous women may be superior to any inert device yet investigated [18). The recent publication of Kesseru et al. (19) containing the enhancement of the contraceptive e f f ~ e n e s s of an Aries copper IUD with Cu-Ni and Cu-Ag combination, togethe~ with the initiation of an intense research by the Battelle group (20) of the device called the Anderson Leaf, a silicone rubber sheath impregnated with Cu and Zn powder, prompt ed us to present our results of studies with Zn and Ag associated with Cu and the effectiveness of a Zn-Cu alloy. The aim of associating other metals specifically to copper is to improve the clinical results of the best active metallic device in actual use. The desired improvements are: (a) to increase the contraceptive activity by reducing the pregnancy rate to 0, as with the Cu-7 and TCu devices, the pregnancy rate is approximately 0.9 to 2 per 100 women years in the first year of use (15); (b) to decrease the expulsion rates using biochemical and not mechanical retention, that is, using the depressing effects of some metals upon myometrial activity and developing the self-retention concept; (c) to minimize the secondary effects such as excessive bleeding and pain; (d) to maintain the effectiveness of these parameters for no less than 3-5 years; and (e) to demonstrate clinical safety such as was shown with endouterine Cu. Apparently the associated metals which could fulfill some of these aims are combinations of.Cu-Ag and Cu-Zn. Our experience with these metal associations on two plastic vectors that have been extensively studied with copper alone, the T and 7 devices, are presented here. MATERIAL AND METHODS The 7 vector, already extensively described in other publications (9), was used as a carrier. Group 1: A wire alloy of 80% Cu and 20% Zn (100 nun2) were added to its vertical arm. Group 2: adding 40 mm 2 of Ag to the Cu-7 200 devices, as a 0.2 mm diameter wire wound around the superior portion of the vertical arm. Group 3: adding 47 mm 2 of Zn, as a wire of 0.5 mm diameter, wound around the superior portion of the vertical arm of the Cu-7 200 device (Figure I). The T vector, already fully described in other publications (2), was u s e d as a carrier. Group 4: adding to the suver~or portion of the vertical arm, 30 mm 2 of Cu and 47 nun z of Zn as an 0.5 nun diameter wire. Group 5: the same material wire as group 4 only on the inferior portion of the vertical arm. Group 6: in the superior portion of the vertical arm, a wire 0.5 mm in diameter of 47 mm 2 of pure Zn was added (Figure 2).
JULY 1975
VOL. 12 NO. 1
3
CONTRACEPTION
£.=_._~ --
C)
Figure I. ?- to =
31
7Cu-Zn 100mm 2 (alloy)
Figure
33
3~
Cu7 200 Zn 47mm 2
2.
T Zn
47mm 2
uterine
4
Cu7 200 Ag 4 0 m m 2
3'2
C)
fundus
TCu 30mm2-Zn 47mm 2
TCu 30mmm-zn 47mm 2
uterine
uterine
segment
JULY 1975
fundus
VOL. 12 NO. 1
CONTRACEPTION
The patients enrolled in this study were essentially multiparous and the insertions were performed after a menstrual period. The number of patients included in each group was: Group 1 = 492; Group 2 = 449; Group 5 = 243; Group 4 = 311; Group 5 = 214; and Group 6 = 191. All the groups with the exception of Group 6 were analyzed by the life table method. The exception was not qualified for precise analysis as the patients in this group had less than 6 months of exposure. Endometrial biopsies with stained hematoxylin-eosine were performed in all the groups in different periods of the cycle and with different periods of exposure, all less than one year. The results of groups 4, 5 and 6 have been descirbed in a previot publication (2). In group I, 50 endometrial biopsies were performed; in group 2, 45 biopsies and in group 3, 46 biopsies were performed.
RESULTS The results are summarized in Tables I and II~ The clinical experiments performed with the T vector demonstrate that the Cu-Zn association (30 m ~ C u and 47 mmZZn) localized in the uterir fundus reduced the pregnancy rate to 0 in the first year of use. Pregnancies occurred when the Zn had completely dissolved (the first pregnancy occurred in the ISth ordinal month). When this component is localized in the inferior segment of the vector, the pregnancy rate is 4.8. The statistical analysis was performe according to Tietze and Lewit (21). The clinical experiments performed with the 7 vector indicat that: a) the addition of 40 mm 2 of Ag to the Cu-7 200 device apparently antagonizes its contraceptive effectiveness without improving any of the other important clinical parameters significantly (Table If); b) a Cu-Zn alloy, I00 mm 2 in surface area, does not significantly reduce the pregnancy rate in the first year (Table If); and c) sufficient experience has not been accumulated with the combination of Cu-7 200 plus 47 m ~ of Zn to determine its total effectiveness, but the preliminary results indicate a definite reduction of pregnancies in this group. Due to the histological alterations found in the users of TCu 30 mm2,Zn 47 m ~ and TZn 47 m ~ devices described in a previous publication (2), special care was taken when observing the histological patterns presented in groups 1 and 3. Of the 96 biopsies performed in this group, no pathological alterations were observed, but some functional modifications were found; of the 40 biopsies performed in the secretory period, II of them were characterized by a late secretory maturation in comparison with the day of the cycle. Nevertheless, these observations must be considered preliminary, as the patients have less than one year of use.
JULY 1975
VOL. 12 NO. 1
5
CONTRACEPTION
TABLE I CUMMULATIVE
RATES OF EVENTS AND CLOSURES PER i00 USERS
BY TYPE OF TERMINATION T-CuZn
(UTERINE FUNDUS),
T-Zn
FOR THE DEVICES
T-CuZn
(UTERINE FUNDUS)(Cu
(UTERINE SEGMENT),
30 mm 2 Zn 47 mm 2)
ONE YEAR OF USE
T-CuZn ~-~ne fundus)
T-CuZn ~6t-~ne segment)
T-Zn -~u-~rine fundus)
0.0±i.i(*)
4.8±2.9(*)
3.1±2.7(*)
3.1±2.0(*) 0.3
1.4±1.6(*) 0.5
1.8±2.0(*) 0.0
2.4 0.3 2.0 2.7 0.3 1.8
2.3 I.I 2.2 5.1 0.0 4.7
1.6 1.2 5.0 2.4 0.6 4.1
0.0
4.8
3.1
1.7 0.3
0.0 0.5
1.2 0.0
1.7 0.3 2.0 2.4 0.3
1.9 I.I 2.2 5.1 2.1
1.6 1.2 4.5 2.4 0.6
rents
Pregnancies Expulsions First Later Removals Bleeding Pain PID Other medical Personal relevant Planning pregnancy Relevant closures
Pregnancy Expulsions First Later Removals Bleeding Pain PID Other medical Personal relevant Continuation
rate
Women months
of use
Initial
insertions
91.3
82.3
5,165.5
1,298.5
511
214
1,829.5 191
t)
Exact calculation
t)
This value is low due to removals at investigator's choice because of high risk of pregnancy
6
for 95% confidence
85.4 (**)
interval
JULY 1975
VOL. 12 NO. 1
CONTRACEPTION
TABLE II CUMULATIVE RATES OF EVENTS AND CLOSURES PER I00 USERS BY TYPE OF TERMINATION FOR THE DEVICES Cu7-200 Ag 40mm 2, 12 MONTHS OF USE Cu7 Zn 100mm2(alloy 80% Cu ~ 20% Zn) ll MONTHS OF USE
Cu7 200 Ag 40mm m Cu7 Zn 100mm 2 12 months Alloy 80% Cu 20% Zn II months Events Pregnancies Expulsions First Later Removals Bleeding Pain PID Personal relevant Planning pregnancy Investigator's choice
5.0_+2.2*
3.1+1.6"
7.7_+2.6* 1.6
5.5±2. i* 0.7
2.2 1.5 0.7 i.O 3.0 0.2
0.8 0.8 0.2 0.0 2.3 0.6
S.O
3.1
3.8 1.3
1. o.
2.2 1.s 0.7 1.0 0.0 0.2
0 0 0 0 0 0
Revevant closures Pregnancy Expulsions First Later Removals Bleeding Pain PID Personal relevant Other medical Investigator's choice Total closures
IS .7
7.
Continuation rate
84 .3
92.
4 , 2 S I ,0
2,776.
Women months of use Number of insertions
449
492
*95% confidence limits
J U L Y 1975
V O L . 12 N O . 1
7
CONTRACEPTION
DISCUSSION The experiments we have performed up to now indicate that the association of certain metals, such as Cu and Ag do not potentiate the contraceptive action of Cu, as the rates of pregnancy on a 7 vector were increased from about 2 to 5 in the first year of use. Kesseru et al.(19) reported a 0 pregnancy rate with a Cu-Ag IUD with l~6--~tients, with 1,306 months of exposure. A plastic vector names Aries, which was used in their study, when used with no active component had a relatively high rate of contraceptive activity, 4.4 in comparison with the plastic T alone. The 0 pregnancy rate found in the above study is probably due to the insufficient months of observation. Vectors of large surface areas such as the Aries or Loop D cannot be used to demonstrate potentiation of contraceptive activity with metals due to the fact that the high leucocytic mobilization produced by the vector alone probably overcomes any action of the cations in the uterine milieu, without resulting in an improvement of the effectiveness of the metal carrying IUDs [7). The alloy, Cu 80% and Zn 20%, with i00 m m 2 surface area did not significantly increase the contraceptive rate of an equivalent surface of Cu alone. This finding might be due to the fact that the solubility of an alloy in the uterine milieu could be extremely low and impossible to.predict in an in vitro experiment, as the quantitative release of each of these cations is unknown. Many different combinations must be tried in vivo before the optimal proportion of the alloy can be achiev-'6~. The combination that presents the most potential is the association of 2 pure metals, Cu and Zn, with which a 0 pregnancy rate was obtained when they are localized near the uterine fundus. The exact quantification and precise optimal localization in the uterine cavity of each of these metals requires further study. The other factors to be intensely investigated are the demonstration of the safety of endouterine Zn and the quantification of other secondary effects that lead to discontinuation of the method, such as excess bleeding and pain. Furthermore, in order to determine whether the clinical effects noted with this Cu-Zn combination are actually due to effects of the metal and not optimal placement of the IUD, randomized comparative clinical trials with this device and pure C u b e a r i n g IUDs needs to be performed.
8
JULY 1975 VOL. 12 NO. 1
CONTRACEPTION
CONCLUSIONS I.
The only pure metals that could produce a 0 pregnancy rate in our experience are a combination of Cu and Zn placed near the fundus of the uterus.
2.
The use of Zn and Cu alloys ~resents complex problems of dissolution in the uterine mllieu that require further investigation. REFERENCES
i.
Zipper, J., Medel, M. and Prager, R.: Suppression tility by intrauterine copper and zinc in rabbits. Obstet. Gynec. 105:529, 1969.
Z.
Zipper, J.,Tatum, H.J., Medel, M., Pastene, L and Rivera, M.: Human fertility control through the use of endouterine metal antagonists of trace elements (EMATE). Fifteenth Nobel Symposium on Control of Human Fertility, 199, 1970.
3.
Chang, C.C.,Tatum, H.J. and Kincl, F.A.: The effect of intrauterine copper and other metals on implantation in rats and hamsters. Pertil. Steril. 21:274, 1970.
4.
Tatum, H.J.: Copper-bearing Obstet. Gynec. 17:95, 1974.
5.
Medel, M., Espinoza, C. and Zipper, J.: Preliminary observation on the effects of copper, zinc and polyethylene IUFB on the uterine motility of the rabbit. Contraception 5:205, 1974.
6.
Salgo, M.P. and Oster, G.: hibition of the rat uterus.
7.
Lippes, J., Zielezny, M., Ferro, P. and Sultz, H.: The effect of increasing copper on Loop A and comparisons with the copper T-200 and Loop D-plain. IUD Workshop, Battelle, October 18-20, 1975, Seattle, Washington.
8.
Stewart, W.C., Gibor, Y., Deysach, L. and Nissen, C.: Clinical studies with the Cu 7: A comparison of results in parous and nulliparous women. Clinical Proceedings of the International Planned Parenthood Federation. SouthEast Asia and Oceania Regional Medical and Scientific Congress, Sydney, 14-18 August, 1972. Published by the Australian and New Zealand Journal of Obstetrics and Gynecology.
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intrauterine
devices.
of ferAm. J.
Clin.
Copper stimulation and inPertil. Steril. 25:113, 1974.
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CONTRACEPTION
Z i p p e r , J . , Medel, M., S e g u r a , R. and T o r r e s , L . : Biological action of copper. Development o f a new t y p e o f intrauterine contraception Cu 7. Clinical Proceedings IPPF. South-East Asia and Oceanic Congress, pp. 193, 1972. Australian and New Zealand Journal of Obstetrics and Gynecology. Aedo, A.R. and Zipper, J.: Effect of copper intrauterine devices (IUDs) of estrogen and progesterone uptake by the rat uterus. Fertil. Steril. 24:345, 1973. Kesseru, E. and Camacho-Ortega, P.: Influence of metals on in vitro sperm migration in the human cervical mucus. Contraception 6:231, 1973. Croxatto, H.B., Faundes, A. and Medel, M.: Studies on sperm migration in the human female genital tract. Colloques IN$ERM 26, 1973. Kesseru, E. and Leon, F.: Effect of different solid metals and metallic pairs on human sperm motility. Int. J. Fertil., in press. Zipper, J. and Medel, M.: Factors that limit the efficiency of copper-carrying IUDs. IUD Workshop, Battelle, October 18-20, 1973, Seattle, Washington, In press. Steward, W.C.: The copper 7 device. Presented at the VI Reunion de la Asociacion Latinoamericana de Investigaciones en Reproduccion Humana, Lima, Peru, August 25-28, 1974. 6
Copper IUD protects never-pregnant, gest 3:11, 1974.
7.
Mishell, D.R., Jr., Israel, R. and Freid, N.: A study of the copper T intrauterine contraceptive device (TCu 200) in nulliparous women. Am. J. Obstet. Gynec. 116:1092, 1973.
8.
Orlans, B.: Intrauterine devices, performance to date. Population Report, I. December, 1973.
9.
Kesseru, E., Hurtado, H. and Mehe, B.: Copper IUD: Enhancement of its efficacy by addition of silver and nickel. Contraception 9:141, 1974.
0.
Development of improved IUDs. Battelle, Seattle, Washington, Seventh Progress Report, July 1973-January 1974.
i.
Tietze, C. and Lewitt, S.: Recommended procedures for the statistical evaluation o f intrauterine contraception. Studies in Family Planning 4:35, 1973.
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