The mechanism of action of the copper intrauterine device

Abstract

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.