Fertility impairment after mifepristone treatment to rats at proestrus. Actions on the hypothalamic-hypophyseal-ovarian axis.

Accumulated evidence indicates that the antigestagen mifepristone affects the reproductive axis acting on hypothalamic, pituitary, ovarian, and uterine tissues. The purpose of this study was to further investigate which reproductive functions are impaired by the antagonist, critically compromising the reproductive process, leading to unsuccessful pregnancy. Circulating pituitary and ovarian hormones, sexual receptivity, ovulation, and implantation rates were studied in cycling rats receiving a single dose of mifepristone (1 or 10 mg/kg subcutaneously) at 12:00 proestrus, before luteinizing hormone (LH) stimulation of the ovulatory process. Mifepristone-treated rats had decreased preovulatory surges of LH and prolactin (PRL), and hypersecretion of LH, PRL, and progesterone at estrus. The sexual receptivity was dramatically affected by the antagonist as indicated by the profound decrease in the lordosis response evaluated on the night of proestrus. The number of ovulating animals and the number of oocytes recovered from the oviduct on the morning of estrus were not affected by mifepristone. The low number of rats that succeeded in mating with potent males became pregnant. However, they delivered an average of only two pups at parturition, indicating a failure in the implantation of the fertilized ova, as ovulation was not affected by the antagonist at the dose used. We conclude that a dramatic inhibition of the sexual receptivity and unsuccessful implantation, preceded by a reduction on LH and PRL secretion, are the major components leading to fertility impairment after a single dose of mifepristone administered before the preovulatory surge of LH.

PIP: Mifepristone has been demonstrated to act on hypothalamic, pituitary, ovarian, and uterine tissue. To further investigate impairments in reproductive function triggered by this antagonist, circulating pituitary and ovarian hormones, sexual receptivity, ovulation, and implantation rates were studied in cycling Wistar rats receiving a single dose (1 or 10 mg/kg subcutaneously) of mifepristone at 12:00 proestrus, before luteinizing hormone (LH) stimulation of the ovulatory process. Treated rats had decreased preovulatory LH and prolactin (PRL) surges and hypersecretion of LH, PRL, and progesterone as estrus. A profound decrease in the lordosis response on the night of proestrus indicated a dramatic effect on sexual receptivity. There was no affect on the number of ovulating animals and the number of oocytes recovered from the oviduct on the morning of estrus. The few rats who succeeded in mating with potent males became pregnant, but they delivered an average of only two pups, indicating a failure in the implantation of the fertilized ova. These findings suggest that the dramatic inhibition of sexual receptivity and unsuccessful implantation, preceded by a reduction in LH and PRL secretion, are the major factors producing fertility impairment after a single dose of mifepristone before the preovulatory LH surge. factors such as smoking and parity.

Mechanisms of action of intrauterine devices.

The major effect of all intrauterine devices (IUD) is to induce a local inflammatory reaction in the endometrium whose cellular and humoral components are released into the uterine cavity. This inflammatory reaction has a variable effect on the reproductive strategy of the species studied. For example, this foreign body reaction can be localized within the uterus of rodents; and in farm animals it can have striking extrauterine effects. Thus, the action of IUDs in humans cannot be discerned from animals. In humans, copper ions released from Cu-IUDs enhance the inflammatory response and reach concentrations in the luminal fluids of the genital tract that are toxic for spermatozoa and embryos. In women using the IUD, the entire genital tract seems affected, at least in part, because of luminal transmission of the fluids that accumulates in the uterine lumen. This affects the function or viability of gametes, decreasing the rate of fertilization and lowering the chances of survival of any embryo that may be formed, even before it reaches the uterus. Studies on the recovery of eggs from women using IUDs and from women not using contraception show that embryos are formed in the tubes of IUD users at a much lower rate compared with nonusers. This is believed to be the major action of IUDs. Therefore, the common belief that the major mechanism of action of IUDs in women is through destruction of embryos in the uterus (i.e., abortion) is not supported by the available evidence. In Cu-IUD users, it is likely that few spermatozoa reach the distal segment of the fallopian tube, those that encounter an egg may be in poor condition. Thus, the few eggs that are fertilized have little chance for development and their possibility for survival in the altered tubal milieu become worse as they approach the uterine cavity.

PIP: All IUDs induce a local inflammatory reaction that disturbs the functioning of the endometrium and myometrium and changes the microenvironment of the uterine cavity. Moreover, these effects alter signaling between uterus and ovary. The entire genital tract seems affected, at least in part because of luminal transmission of fluids accumulating in the uterine lumen. Copper or progesterone-releasing IUDs may attenuate or accentuate the inflammatory response, disturb the physiology of the gametes in the female genital tract, or destroy the viability of the embryos or endometrial receptivity to implantation. Studies on the recovery of eggs reveal that embryos are formed in the tubes of IUD users at a significantly lower rate compared to non-users. This, rather than the destruction of embryos in the uterus, appears to be the IUD's major mechanism of action.

Early chorionic activity in women bearing inert IUD, copper IUD and levonorgestrel-releasing IUD.

Early chorionic activity was assessed in the premenstrual days by means of serum HCG beta-fraction. As control, a group of women with no contraceptive use was studied; early chorionic activity was detected in 31.8% of the cycles. In the group bearing an inert IUD the incidence was 20%, which did not differ from the control; while in the medicated IUD groups (Cu-IUD and LNG-IUD) the incidences were 4.8% and nil, respectively. Both medicated IUD groups showed a significant difference when compared with the control, as well as the inert IUD groups. The meaning of these findings, pointing out differences in the main mechanism of action between inert and medicated IUDs, is discussed.

PIP: Early chorionic activity was compared in 100 IUD users (inert device, copper IUD, and a levonorgestrel-releasing IUD) and 22 controls through measurement of the serum human chorionic gonadotropin (hCG) beta-fraction. In the control group, 7 (32%) of the 22 women had hCG beta-fraction values indicative of chorionic activity (i.e., 5mIU/ml). In the group of women wearing an inert IUD (Lippes Loop), 8 (20%) were positive for early chorionic activity. In contrast, the incidence of premenstrual chorionic activity signs was very low among women with medicated IUDs: 5% among acceptors of the copper IUD and zero among women in the levonorgestrel-releasing IUD group. In general, elevated premenstrual hCG values are indicative of failed implantation. The high incidence of hCG activity recorded among Lippes Loop acceptors in this study is consistent with the anti-implantation effect postulated for inert devices. In contrast, medicated IUDs appear to act by preventing rather than interrupting implantation and therefore should not be regarded as abortifacient contraceptive agents.

Post-coital oral contraception.

PIP: The observation that estrogens in sufficient dosage given postcoitally may prevent implantation of the ovum have led to studies regarding practical clinical application. Estrogens that appear effective in humans include stilbestrol and ethinyl estradiol orally and estrone parenterally. Mestranol should also be effective as well as ORF-3858. Any estrongenic substance in sufficient dosage would probably prevent implantation. Effective period of administration is only between time of fertilization and implantation or 4 to 6 days following coitus. Test dosages have been 25-50 mg stilbestrol or .5-2 mg esthinyl estradiol daily for 5 days. It is now considered that 2-5 mg ethinyl estradiol would be more effective. In over 100 midcycle exposures there have been no pregnancies. Others have reported failures with inadequate dosage. Injectable estrone, 2-20 mg on alternate days for 3 doses, has also been reported effective. The process of implantation is discussed. Endometrial biopsies have usually revealed a "retarded endometrium," a possible mode of action. Side effects have been those usually associated with estrogens: nausea, vomiting, breast soreness, prolonged menses.^ieng