Review article| Volume 75, ISSUE 6, SUPPLEMENT , S16-S30, June 2007

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Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action


      All intrauterine devices (IUDs) that have been tested experimentally or clinically induce a local inflammatory reaction of the endometrium whose cellular and humoral components are expressed in the tissue and the fluid filling the uterine cavity. Depending on the reproductive strategy of the species considered and the anatomical features and physiologic mechanisms that characterize their reproductive system, the secondary consequences of this foreign body reaction can be very localized within the uterus, as in the rabbit, or widespread throughout the entire genital tract as in women or even systemic as in some farm animals.
      Levonorgestrel released from an IUD causes some systemic effects, but local effects such as glandular atrophy and stromal decidualization, in addition to the foreign body reaction, are dominant. Copper ions released from an IUD enhance the inflammatory response and reach concentrations in the luminal fluids of the genital tract that are toxic for spermatozoa. In the human, the entire genital tract appears affected due to luminal transmission of the noxa that accumulates in the uterine lumen. This affects the function and viability of gametes, decreasing the rate of fertilization and lowering the chances of survival of any embryo that may be formed, before it reaches the uterus.
      The bulk of the data indicate that if any embryos are formed in the chronic presence of an IUD, it happens at a much lower rate than in non-IUD users. The common belief that the usual mechanism of action of IUDs in women is destruction of embryos in the uterus is not supported by empirical evidence.


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        • Ortiz M.E.
        • Croxatto H.B.
        The mode of action of IUDs.
        Contraception. 1987; 36: 37-53
        • Sivin I.
        IUDs are contraceptives, not abortifacients: a comment on research and belief.
        Stud Fam Plann. 1989; 20: 355-359
        • Croxatto H.B.
        • Ortiz M.E.
        • Valdez E.
        IUD mechanisms of action.
        in: Bardin C.W. Mishell D.R. Proceedings from the Fourth International Conference on IUDs. Butterworth-Heinemann, Boston1994: 44-62
        • Ortiz M.E.
        • Croxatto H.B.
        • Bardin C.W.
        Mechanisms of action of intrauterine devices.
        Obstet Gynecol Surv. 1996; 51: S42-S51
        • Stanford J.B.
        • Mikolajczyk R.T.
        Mechanisms of action of intrauterine devices: update and estimation of postfertilization effects.
        Am J Obstet Gynecol. 2002; 187: 1699-1708
        • Doyle L.L.
        • Margolis A.J.
        Intrauterine foreign body. I. Effect on reproductive processes in rat.
        Fertil Steril. 1964; 15: 597-606
        • Parr E.L.
        • Shirley R.L.
        Embryotoxicity of leukocyte extracts and its relationship to intrauterine contraception in humans.
        Fertil Steril. 1976; 27: 1067-1077
        • Barbosa I.
        • Bakos O.
        • Olsson S.E.
        • Odlind V.
        • Johansson E.
        Ovarian function during use of a levonorgestrel-releasing IUD.
        Contraception. 1990; 42: 51-66
        • Barbosa I.
        • Olsson S.E.
        • Odlind V.
        • Goncalves T.
        • Coutinho E.
        Ovarian function after seven years' use of a levonorgestrel IUD.
        Adv Contracep. 1995; 11: 85-95
        • Jonsson B.
        • Landgren B.-M.
        • Eneroth P.
        Effects of various IUDs on the composition of cervical mucus.
        Contraception. 1991; 43: 447-458
        • Nygren K.G.
        • Johansson E.D.B.
        Premature onset of menstrual bleeding during ovulatory cycles in women with an intrauterine contraceptive device.
        Am J Obstet Gynecol. 1973; 117: 971-977
        • Brenner P.F.
        • Cooper D.L.
        • Mishell D.R.
        Clinical study of a progesterone-releasing intrauterine contraceptive device.
        Am J Obstet Gynecol. 1975; 121: 704-706
        • Faundes A.
        • Segal S.J.
        • Adejuwon C.A.
        • Brache V.
        • Leon P.
        • Alvarez-Sanchez F.
        The menstrual cycle in women using an intrauterine device.
        Fertil Steril. 1980; 34: 427-430
        • Fahmy K.
        • el-Gazar A.
        • Eisa I.
        • Ghonaim M.
        • Saad S.
        • Afifi A.
        Levels of serum steroids hormones in intrauterine contraceptive device users.
        Gynecol Endocrinol. 1991; 1: 1-5
        • Johannisson E.
        Mechanism of action of intrauterine devices: biochemical changes.
        Contraception. 1987; 36: 11-22
        • Cuadros A.
        • Hirsch J.G.
        Copper on intrauterine devices stimulates leukocyte exudation.
        Science. 1972; 175: 175-176
        • Ullmann G.
        • Hammerstein J.
        Inhibition of sperm motility in vitro by copper wire.
        Contraception. 1972; 6: 71-76
        • Jecht E.
        • Berstein G.
        The influence of copper on the motility of human spermatozoa.
        Contraception. 1973; 7: 381-401
        • Roblero L.
        • Guadarrama A.
        • Lopez T.
        • Zegers-Hochschild F.
        Effect of copper ion on the motility, viability acrosome reaction and fertilizing capacity of human spermatozoa in vitro.
        Reprod Fertile Dev. 1996; 8: 871-874
        • Hagenfeldt K.
        Intrauterine contraception with the copper-T device. Effect on trace elements in the endometrium, cervical mucus and plasma.
        Contraception. 1972; 6: 37-54
        • Kesseru E.
        • Camacho-Ortega P.
        Influence of metals on in vitro sperm migration in the human cervical mucus.
        Contraception. 1972; 6: 231-240
        • Elstein M.
        • Ferrer K.
        The effect of a copper-releasing intrauterine device on sperm penetration in human cervical mucus in vitro.
        J Reprod Fert. 1973; 32: 109-112
        • Hefnawi F.
        • Kandil O.
        • Askalani A.
        • Serour G.
        Influence of the copper IUD and the Lippes loop on sperm migration in the human cervical mucus.
        Contraception. 1975; 11: 541-547
        • Munuce M.J.
        • Nascimento J.A.A.
        • Rosano G.
        • Faundes A.
        • Bahamondes L.
        Doses of levonorgestrel comparable to that delivered by the levonorgestrel-releasing intrauterine system can modify the in vitro expression of zona binding sites of human spermatozoa.
        Contraception. 2006; 73: 97-101
        • Brache V.
        • Faundes A.
        • Johansson E.
        • Alvarez F.
        Anovulation, inadequate luteal phase and poor sperm penetration in cervical mucus during prolonged use of Norplant implants.
        Contraception. 1985; 31: 261-273
        • Croxatto H.B.
        • Diaz S.
        • Salvatierra A.M.
        • Morales P.
        • Ebensperger C.
        • Brandeis A.
        Treatment with Norplant subdermal implants inhibits sperm penetration through cervical mucus in vitro.
        Contraception. 1987; 36: 193-201
        • Kesseru E.
        • Camacho-Ortega P.
        • Laudahn G.
        • Schopflin G.
        In vitro action of progestagens on sperm migration in the human cervical mucus.
        ICRS J Int Res Commun. 1974; 2: 1152
        • Koch U.J.
        Sperm migration in the human female genital tract with and without intrauterine devices.
        Acta Eur Fertil. 1980; 2: 33-60
        • Ahlgren M.
        Sperm transport to and survival in the human fallopian tube.
        Gynecol Invest. 1975; 6: 206-214
        • Settlage D.S.F.
        • Motoshima M.
        • Tredway D.R.
        Sperm transport from the external cervical os to the Fallopian tubes in women: a time and quantitation study.
        Fertil Steril. 1973; 24: 655-661
        • Tredway D.R.
        • Umezaki C.U.
        • Mishell Jr, D.R.
        • Settlage D.S.
        Effect of intrauterine devices on sperm transport in the human being: preliminary report.
        Am J Obstet Gynecol. 1975; 123: 734-735
        • El-Habashi M.
        • El-Sahwi S.
        • Gawish S.
        • Osman M.
        Effect of Lippes loop on sperm recovery from human Fallopian tubes.
        Contraception. 1980; 22: 549-555
        • Moyer D.L.
        • Rmdusit S.
        • Mishell D.R.
        Sperm distribution and degradation in the human female reproductive tract.
        Obstet Gynecol. 1970; 35: 831-840
        • Sagiroglu N.
        Phagocytosis of spermatozoa in the uterine cavity of woman using intrauterine device.
        Int J Fertil. 1971; 16: 1-14
        • Croxatto H.B.
        • Faundes A.
        • Medel M.
        • et al.
        Studies on sperm migration in the human female genital tract.
        in: Hafez E.S.E. Thibault C.G. The biology of spermatozoa. Karger AG, Basel1975: 56-64
        • Aref I.
        • Kandil O.
        • El-tagi A.
        • Morad M.R.
        Effects of non-medicated and copper IUDs on sperm migration.
        Contracept Deliv Syst. 1983; 4: 203-206
        • Malkani P.K.
        • Sujan S.
        Sperm migration in the female reproductive tract in the presence of intrauterine devices.
        Amer J Obstet Gynecol. 1964; 88: 963-964
        • Morgenstern L.L.
        • Orgebin-Crist M.-C.
        • Clewe T.H.
        • Bonney W.A.
        • Noyes R.W.
        Observations on spermatozoa in the human uterus and oviducts in the chronic presence of intrauterine devices.
        Amer J Obstet Gynecol. 1966; 96: 114-118
        • Wildt L.
        • Kissler S.
        • Licht P.
        • Becker W.
        Sperm transport in the human female genital tract and its modulation by oxytocin as assessed by hysterosalpingoscintigraphy, hysterotomography, electrohysterography and Doppler sonography.
        Hum Reprod Update. 1998; 4: 655-666
        • Mandelin E.
        • Koistinen H.
        • Koistinen R.
        • Affandi B.
        • Seppala M.
        Levonorgestrel-releasing intrauterine device-wearing women express contraceptive glycodelin A in endometrium during midcycle: another contraceptive mechanism?.
        Hum Reprod. 1997; 12: 2671-2675
        • Alvarez F.
        • Brache V.
        • Fern��ndez E.
        • et al.
        New insights on the mode of action of intrauterine contraceptive devices in women.
        Fertil Steril. 1988; 49: 768-773
        • Armstrong E.G.
        • Ehrlich P.H.
        • Birken S.
        Use of a highly sensitive and specific immunoradiometric assay for detection of human chorionic gonadotropin in urine of normal, nonpregnant and pregnant individuals.
        J Clin Endcrinol Metab. 1984; 59: 867-874
        • Braunstein G.D.
        • Rasor J.
        • McCready J.
        • Wade M.E.
        Varying bioactive to immunoactive ratios of the human chorionic gonadotropin-like substance present in normal human tissues.
        J Clin Endocrinol Metab. 1984; 58: 170-175
      1. Segal S.J. Chorionic gonadotropin. Plenum Press, New York1980
        • Videla-Rivero L.
        • Etchepareborda J.J.
        • Kesseru E.
        Early chorionic activity in women bearing inert IUD, copper IUD and levonorgestrel releasing IUD.
        Contraception. 1987; 36: 217-226
        • Canfield R.E.
        • O'Connor J.F.
        • Birken S.
        • Krichevsky A.
        • Wilcox A.J.
        Development of an assay for a biomarker of pregnancy and early fetal loss.
        Env Health Persp. 1987; 74: 57-66
        • Wilcox A.J.
        • Weinberg C.R.
        • Wehmann R.E.
        • Armstrong E.G.
        • Canfield R.E.
        • Nisula B.C.
        Measuring early pregnancy loss: laboratory and field methods.
        Fertil Steril. 1985; 44: 366-374
        • Wilcox A.J.
        • Weinberg C.R.
        • Armstrong E.G.
        • Canfield R.E.
        Urinary human gonadotropin among intrauterine device users: detection with a highly specific and sensitive assay.
        Fertil Steril. 1987; 47: 265-269
        • Morton H.
        • Rolfe B.
        • Clunie G.J.A.
        • Anderson M.J.
        • Morrison J.
        An early pregnancy factor detected in human serum by the rosette inhibition test.
        Lancet. 1977; 1: 394-397
        • Orozco C.
        • Perkins T.
        • Clarke F.M.
        Platelet-activating factor induces the expression of early pregnancy factor activity in female mice.
        J Reprod Fertil. 1986; 78: 549-555
        • Morton H.
        • Rolfe B.E.
        • Cavanagh A.C.
        Ovum factor and early pregnancy factor.
        Curr Top Dev Biol. 1987; 23: 73-92
        • Sueoka K.
        • Dharmarajan A.M.
        • Miyazaki T.
        • Atlas S.J.
        • Wallach E.E.
        In-vivo and in-vitro determination of components of rabbit early pregnancy factors.
        J Reprod Fertil. 1989; 87: 47-53
        • Rolfe B.E.
        Detection of fetal wastage.
        Fertil Steril. 1982; 37: 655-660
        • Smart Y.C.
        • Fraser I.S.
        • Clancy R.L.
        • Roberts T.K.
        • Cripps A.W.
        Early pregnancy factor as a monitor for fertilization in women wearing intrauterine devices.
        Fertil Steril. 1982; 37: 201-204
        • Bose R.
        • Cheng H.
        • Sabbadini E.
        • McCoshen J.
        • MaHadevan M.M.
        • Fleetham J.
        Purified human early pregnancy factor from preimplantation embryo possesses immunosuppresive properties.
        Am J Obstet Gynecol. 1989; 160: 954-960
        • Nahhas F.
        • Barnea E.
        Human embryonic origin early pregnancy factor before and after implantation.
        Am J Reprod Immunol. 1990; 22: 105-108
        • Cavanagh A.C.
        • Morton H.
        • Athanasas-Platsis S.
        • Quinn K.A.
        • Rolfe B.E.
        Identification of a putative inhibitor of early pregnancy factor in mice.
        J Reprod Fertil. 1991; 91: 239-248
        • Athanasas-Platsis S.
        • Morton H.
        • Dunglison G.F.
        • Kaye P.L.
        Antibodies to early pregnancy factor retard embryonic development in mice in vivo.
        J Reprod Fertil. 1991; 92: 443-451
        • Croxatto H.B.
        • Fuentealba B.
        • D��az S.
        • Pastene L.
        • Tatum H.J.
        A simple nonsurgical technique to obtain unimplanted eggs from human uteri.
        Am J Obstet Gynecol. 1972; 112: 662-668
        • Croxatto H.B.
        • D��az S.
        • Fuentealba B.
        • Croxatto H.-D.
        • Carrillo D.
        • Fabres C.
        Studies on the duration of egg transport in the human oviduct. I. The time interval between ovulation and egg recovery from the uterus in normal women.
        Fertil Steril. 1972; 23: 447-458
        • D��az S.
        • Ortiz M.E.
        • Croxatto H.B.
        Studies on the duration of ovum transport by the human oviduct. III. Time interval between the Luteinizing hormone peak and egg recovery by transcervical flushing of the uterus in normal women.
        Am J Obstet Gynecol. 1980; 137: 116-121
        • Croxatto H.B.
        The duration of egg transport and its regulation in mammals.
        in: Coutinho E.M. Fuchs F. The physiology and genetics of reproduction. vol II. Plenum Publishing Corporation, New York1974: 159-166
        • Croxatto H.B.
        • Ortiz M.E.
        Oocyte pickup and oviductal transport.
        in: Capitanio G.L. Asch R.H. De Cecco L. Groce S. From basics to clinics. Raven Press, New York1989: 137-147
        • Croxatto H.B.
        • Carril M.
        • Cheviakoff S.
        • et al.
        Time interval between LH peak and ovulation in women.
        in: Ebling F.J.G. Henderson E.W. Biological and clinical aspects of reproduction. Excerpta Medica, Amsterdam1976: 282-284
        • Ortiz M.E.
        • Croxatto H.B.
        Observations on the transport, aging, and development of ova in the human genital tract.
        in: Talwar G.P. Recent advances in reproduction and regulation of fertility. Elservier/North Holland Biomedical Press, New York1979: 307-317
        • Ortiz M.E.
        • Salvatierra A.M.
        • L��pez J.
        • Fern��ndez E.
        • Croxatto H.B.
        Postovulatory aging of human ova. I. Light microscopic observations.
        Gamete Res. 1982; 6: 11-17
        • Ortiz M.E.
        • Lucero P.
        • Croxatto H.B.
        Postovulatory aging of human ova. II. Spontaneous division of the first polar body.
        Gamete Res. 1983; 7: 268-276
        • Hurst P.R.
        • Wheeler A.G.
        • Eckstein P.
        A study of uterine embryos recovered from rhesus monkeys fitted with intrauterine devices.
        Fertil Steril. 1980; 33: 69-76
        • Ortiz M.E.
        • Lucero P.
        • Herrera E.
        • Croxatto H.B.
        Transport and development of eggs in primates.
        in: Puri Ch.P. Van Look P.F.A. Current concepts in fertility regulation and reproduction. Wiley Eastern Limited, New Delhi1994: 355-377
        • Clewe T.H.
        • Morgenstern L.L.
        • Noyes R.W.
        • Bonney Jr, W.A.
        • Burrus S.B.
        • DeFoe V.J.
        Searches for ova in the human uterus and tubes. II. Clinical and laboratory data on nine successful searches for human ova.
        Am J Obstet Gynecol. 1971; 109: 313-334
        • Noyes R.W.
        • Clewe T.H.
        • Bonney W.A.
        • Burrus S.B.
        • De Feo V.J.
        • Morgestern L.L.
        Searches for ova in the human uterus and tubes. I. Review, clinical methodology, and summary of findings.
        Am J Obstet Gynecol. 1966; 96: 157-167
        • Avenda��o S.
        • Croxatto H.-D.
        • Pereda J.
        • Croxatto H.B.
        A seven-cell human egg recovered from the oviduct.
        Fertil Steril. 1975; 26: 1167-1172
        • Larsson B.
        • Ljung B.
        • Hamberger L.
        The influence of copper on the in vitro motility of the human fallopian tube.
        Am J Obstet Gynecol. 1976; 125: 682-690
        • Myatt L.
        • Bray M.A.
        • Gordon D.
        • Morley J.
        Macrophages on intrauterine contraceptive devices produce prostaglandins.
        Nature. 1975; 257: 227-228
        • Tursi A.
        • Mastrorilli A.
        • Ribatti D.
        • Loiudice L.
        • Contino R.
        • Claudatus J.
        Possible role of mast cells in the mechanism of action of intrauterine contraceptive devices.
        Am J Obstet Gynecol. 1984; 148: 1064-1066
        • Randic L.
        • Haller H.
        • Susa M.
        • Rukavina D.
        Cells adherent to copper-bearing intrauterine contraceptive devices determined by monoclonal antibodies.
        Contraception. 1990; 42: 35-42