Mario Medel

Human Fertility Control by Transvaginal Application of Quinacrine on the Fallopian Tube

A suspension of the cytotoxant quinacrine is instilled into the endometrial cavities to occlude the proximal fallopian tube of women. Rat experiments had shown that obstruction of the uterus occurred because of hyperplasia of the endometrium increased with dose and was reversible with exogenous estradiol or progesterone. One group of 85 patients received up to 3 doses with 2 ml of 250 mg quinacrine-HCl in water suspension. Group B (37 patients) received up to 2 treatments with 4 ml of a 1 gm suspension. Suspensions were given with a biopsy cannula with an attached 10 ml syringe endometrially within 1 min 3 or 4 days after the menstrual flow. If patency of the tubes were verified by CO2 insufflation or hysterosalpingography treatment was stopped. Biopsies were studied histologically from 4 patients who subsequently had salpingectomy and 20 others. Sixty out of 85 in Group A (24 after 1 dose) were occluded and pregnancy rate was 8.6 per 100 woman-years after 2 years. Menstruation was normal. Occlusion and histologic changes took place in the cornual tube lessening for 2-3 mm. Occlusion occurred in 24/37 in Group B after 1 dose and 5/9 who had 2 doses. Pregnancies appeared only in those whose tubes remained patent. No peritonitis pain or ectopic pregnancies were recorded. Rat experiments point to the acridine nucleus as the active moeity since proflavine but not chloroquine or riboflavine produced hyperplasia of the endometrium.

Alterations in fertility induced by unilateral intrauterine instillation of cytotoxic compounds in rats

Abstract Cytotoxic agents, cadmium, iodoacetate, thio-TEPA, podophyllin, colchicine, and alcohol, were instilled in one uterine horn of the rat to observe their subsequent effect on fertility. Cadmium and iodoacetate interfere with implantation in both horns without altering ovulation for periods of 1 to 2 months. Thio-TEPA produces a unilateral effect for periods of 2 months. With alcohol this unilateral effect is prolonged. In every group histologic changes are detailed. Reversibility is complete in every group except the alcohol group.

Transvaginal chemical sterilization: Clinical use of quinacrine plus potentiating adjuvants

Abstract Six years of experience with the use of transvaginal quinacrine as an obliterating agent of the intramural portion of the fallopian tube are presented. Fifteen different forms of treatment using various dosages of quinacrine, alone as well as a combination of quinacrine with several other pharmacological agents were studied. The purpose of these studies was to increase the rate of tubal obstruction, with 1 or 2 instillations of solution. The total experience is based on 638 patients who received treatment according to a prefixed plan. There was a total of 14,677 women months of observation and 437 patients were diagnosed as having tubal obstruction with CO2 insufflation. Out of this group of 437, 50 pregnancies were observed, none of them ectopic, for a Pearl Index of 4. 10. The most effective treatment regimen, quinacrine + xylocaine, with and without epinephrine, after the second instillation had an obstruction rate of 94%. Most of the pregnancies in obstructed patients occurred in the first year and appeared to be due to incomplete obstruction of the oviduct.

Biologic Changes Induced by Unilateral Intrauterine Instillation of Quinacrine in the Rat and Their Reversal by Either Estradiol or Progesterone

Quinacrine had previously been found to induce alterations in the en dometrium of the rat and also had been safely employed in humans for its carcinostatic effect. Single injections of from 5 to 40 mg in a .2 ml aqueous suspension were instilled into the right uterine horn of each rat. The animals were mated at different intervals daily vaginal smears made and implantation sites and corpora lutea recorded on Days 9 or 10 after coitus. In another group a search for blastocysts was made on Day 5 after injections of 20 mg or 40 mg. In a third group either estradiol benzoate 50 mcg or progestogen 500 mcg was injected at varying times from 24 hours to 28 days after the quinacrine. Animals were sacrificed 10 days after the last hormone injection. Doses of quinacrine below 20 mg did not alter the fertility of the rats. With larger doses there was a gradual time-related recovery with regard to the number of implantations. This recovery paralleled restoration of uterine patency. Another antimalarial drug chloroquine had no effect on implantation rates. Microscopic studies of some uterine horns of rats treated with 20 mg of quinacrine showed a proliferative reaction and complete obstruction of the lumen. Quinacrine crystals were observed within the mass of foreign-body giant cells and stroma cells for as long as 90 days. These changes after 20 mg reversed spontaneously after 3 months but those after 40 mg doses persisted. Use of talc powder as a particulate matter did not produce any tissue reaction. This action of quinacrine was prevented by either estrogen or progestogen when injected within a short time after quinacrine instillation. In these cases the uterine lumina were patent and the uterine epithelium showed typical changes induced by either estrogen or progestogen. Also the luminal patency was restored when the hormones were administered when obstructed uteri were present.

Copper determination and localization in different morphologic components of human endometrium during the menstrual cycle in copper intrauterine contraceptive device wearers

Comparisons were made of endometrial biopsies performed at random during the 4 phases of the menstrual cycle and after different periods of use on women wearing TCU-120 sq.mm IUD devices, users of plain T devices (minus Cu), and patients without IUDs to determine the localization of Cu delivered by the IUD and the leukocytic infiltration rate. Cu was found to localize in the secretory vacuoles of the endometrial epithelial cells during the progestational phase and was absent during the estrogenic phase indicating that a rise in Cu concentration is progesterone-dependent. No Cu was detected 7 or more days after extraction of the device. No increase in leukocytic infiltration was found in TCU-120 sq.mm device wearers suggesting that the contraceptive mechanism of Cu is not related to leukocyte concentration.

FOUR YEARS EXPERIENCE WITH THE Cu7 200 DEVICE- ENDOUTERINE COPPER IN FERTILITY CONTROL

Four years of experience with the Cu7 200 device have been completed. The 516 initial women studied accumulated a total of 17,554 months of observation. The most relevant events were: the net annual pregnancy rates, in four successive years of observation, were 2.3, 1.8, 2.1 and 0.9; rates for expulsions were 4.7 0.8, 0.0, and 0.4; and rates for bleeding/pain were 1.6, 2.1, 1.1, and 0.9, respectively, for each year. The quantitative gravimetric analysis of the remaining copper on the device, after four years of use, indicated that the loss of the metal is less than 30% of the original material; therefore the contraceptive activity of the device will continue for some years more. The mechanism of action of endouterine copper is discussed.

The clinical efficacy of the repeated transcervical instillation of quinacrine for female sterilization.

Zipper, J., Medel, M., Goldsmith, A., Edelman, D., Pastene, L. and Rivera, M. (Dept. of Physiology & Biophysics, School of Medicine, University of Chile, Santiago, and Dept. of Obstetrics & Gynecology, Hospital Sotero del Rio, Puente Alto, Chile, and International Fertility Research Program, Research Triangle Park, North Carolina 27709, USA). The clinical efficacy of the repeated transcervical instillation of quinacrine for female sterilization.

Preliminary observations on the effects of copper, zinc and polyethylene I. U. F. Bs. on the uterine motility of the rabbit.

Abstract The action of copper and zinc upon myometrial activity of the rabbit uterus was studied indirectly by observing the behaviour of “inert” (polyethylene segments) and “active” (copper and zinc wires) IUFBs upon the uterine activity of estrous and pregnant does. It was observed that “inert” foreign bodies were rapidly expelled from the rabbit uterus whereas the “active” ones were retained and transported in the direction of the utero-tubal junction. The differences observed were statistically significant and support the idea that metal IUFBs affect myometrial function of the rabbit uterus. The mechanism possibly responsible for this change is discussed.

Long-term use effectiveness of the CU-7-200 IUD.

Copper‐containing IUDs have been demonstrated to be as good, if not better, than other presently used inert devices. There is, however, no consensus on the duration of contraceptive effectiveness of copper‐containing IUDs. The long‐term contraceptive effectiveness of one copper‐containing IUD, the CU‐7‐200 Gravigard®, is evaluated in this report on 514 patients. IUDs were inserted in the intermenstrual period and patients were followed up for as long as 63 months. The probability of pregnancy, expulsion, or removal for medical reasons did not increase with increasing duration of IUD use, but instead appeared to slightly decrease with increasing duration of IUD use. The results of this study indicate that the CU‐7‐200 continues to be an effective contraceptive for at least five years after insertion.

Reversibility of the contraceptive action of copper and zinc in the rat and rabbit

Abstract Segments of metallic copper and zinc are potent contraceptives when placed within the uterine lumen of several species of animals, including the human. The reversibility of this contraceptive action was studied in rats and rabbits by removing the intrauterine devices after fertilization had taken place. Rats and rabbits had copper or zinc wires or nylon thread inserted in the lower third of the right horn. Rats were mated either shortly after surgery or one month later and rabbits within the first or third month of treatment. All devices were removed on day two of pregnancy in rats and on day three in rabbits and corpora lutea and implantation sites were counted on day ten. No statistical differences in fertility were found between groups in both species (P > 0.05), demonstrating the same degree of reversibility of the contraceptive effect of nylon (inert) and metallic (active) IUD S . Fertility of the treated horn after removal of the IUD was significantly lower than that of the control horn in the rat but not in the rabbit. The importance of the rapid reversibility of copper contraceptive activity is enhanced by the use of this metal in human contraception. It is concluded that the continuous liberation of the metal ions within the uterine lumen is necessary for their sustained contraceptive action.