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Low-dose antiprogestin administration has been proposed as a new contraceptive modality to interference with endometrial receptivity without disturbing ovarian function. The effects of 1 mg/day mifepristone for 150 days on the menstrual cycle were assessed in 21 surgically sterilized women. The aim was to study each woman for one control cycle and during months 1, 3 and 5 of treatment. Ovulation, endometrial thickness, serum oestradiol and progesterone, urinary luteinizing hormone, endometrial morphology and cervical mucus were assessed. Luteal phase progesterone concentrations were observed in 36 of the 60 treated months assessed and less frequently as treatment progressed. The bleeding pattern was regular in most biphasic cycles, while prolonged interbleeding intervals or no bleeding were associated with monophasic cycles. Altered endometrial morphology was found in all cases irrespective of the occurrence of luteal activity. Increased endometrial thickness and dilated glands were observed in 25 and 34% respectively of the monophasic cycles. Mifepristone, 1 mg/day, interferes with endometrial development while allowing the occurrence of biphasic ovarian cycles and regular bleeding. However, it also prevents ovarian cyclicity in a high proportion of treated months, and this is associated with increased endometrial growth in some women, which may be of concern.

PIP: Low-dose antiprogestin administration has been proposed as a new contraceptive modality that interferes with endometrial receptivity without disturbing ovarian function. To explore this potential, the effects on the menstrual cycle of 1 mg/day of mifepristone for 150 days were assessed in 21 surgically sterilized women from Santiago, Chile. Control cycles were biphasic in all 21 women and ovulatory in 20 women. Luteal phase progesterone concentrations were observed in 36 of the 60 treatment months (1, 3, and 5) assessed. The proportion of ovulatory cycles was highest during month 1 and decreased progressively with treatment. 40% of treatment cycles were monophasic and bleeding cyclicity was altered in 57%. Prolonged inter-bleeding intervals or no bleeding occurred in monophasic cycles. Endometrial morphology was altered in all cases, regardless of the occurrence of luteal activity. Increased endometrial thickness and dilated glands were recorded in 25% and 34%, respectively, of the monophasic cycles. These findings suggest that 1 mg of mifepristone interferes with endometrial development while allowing biphasic ovarian cycles and regular bleeding. Whether these endometrial alterations are sufficient to prevent implantation remains to be established. The long-term effect of prevention of ovarian cyclicity and the associated increased endometrial growth recorded in some women require further investigation.

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RESUMO

The efficacy of a low dose of mifepristone, 5 mg/day for the first 15 days of the menstrual cycle, followed by medroxy-progesterone acetate (MPA), 10 mg/day for the next 13 days, for inhibiting ovulation was assessed in ten volunteers who were treated for three successive cycles. Hormonal determinations in blood and urine samples, ovarian ultrasonography and an endometrial biopsy taken on day 21-24 of the third treatment cycle were used to monitor the cycles. Ovulation was confirmed in 11 of the 30 treated cycles and, in these 11, the LH peak and follicular rupture occurred during MPA treatment periods. Out of 19 anovulatory cycles, 16 had no increase in progesterone levels and another 3 developed a luteinized unruptured follicle. Progestin administration induced secretory changes in the endometrium, but irregular or delayed development was found. Regular withdrawal bleeding occurred in all subjects. These data indicate that the sequential regimen can suppress ovulation while maintaining regular bleeding but increased efficacy is needed for phase II clinical trials.

PIP: The efficacy of a low dose of mifepristone, 5 mg/day for the first 15 days of the menstrual cycle, followed by medroxyprogesterone acetate (MPA), 10 mg/day for the next 13 days, for inhibiting ovulation was assessed in 10 Chilean volunteers who were treated for 3 successive cycles. They were healthy, surgically sterilized women with a mean age of 36.6 years and mean weight of 58.6 kg. Hormonal determinations in blood and urine samples, ovarian ultrasonography and an endometrial biopsy taken on days 21-24 of the third treatment cycle were used to monitor the cycles. Treatment inhibited ovulation during the 3 treatment cycles in 5 women. The regimen was partially effective in 3 women and totally ineffective in another 2 women. Ovulation was confirmed in 11 of the 30 treated cycles, and, in these 11, the luteinizing (LH) peak and follicular rupture occurred during MPA treatment periods. Out of 19 anovulatory cycles, 16 had no increase in progesterone levels and another 3 developed a luteinized unruptured follicle. Among the anovulatory cycles, 3 cycles presented a biphasic hormonal profile. In these 3 cycles the luteal phase progesterone level were much lower than in baseline cycles and they were associated with unruptured follicles. The other 16 cycles had a monophasic hormonal profile with no increase in progesterone levels in spite of a delayed rise in LH level. Progestin administration induced secretory changes in the endometrium, but irregular or delayed development was found. Only 9 post-treatment cycles were followed and 5 of these were ovulatory, 1 of them without a detectable LH midcycle peak. Regular withdrawal bleeding occurred in all subjects. These data indicate that the sequential regimen can suppress ovulation while maintaining regular bleeding, but increased efficacy is needed for phase II clinical trials.

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RESUMO

This study was designed to assess the features and conditions for endometrial bleeding induction with the synthetic antiprogestin and antiglucocorticoid RU 486 during hCG-induced prolongation of the luteal phase. Eighteen healthy, surgically sterilized women and another five women with an intrauterine contraceptive device (IUD) participated. All subjects received hCG which was injected daily in increasing doses (500 to 15,000 IU) from day 9 to day 15 of the luteal phase. Ten subjects received hCG alone, and groups of three to 16 subjects received hCG combined with RU 486 (25, 50, 100, 200 or 400 mg/day). RU 486 administration was commenced on day 12 following the LH surge and given either for 1, 4 or 7 consecutive days. In certain cycles, tamoxifen (20 mg/day) was given for 4 consecutive days with hCG, or with hCG and RU 486. All treatment cycles were separated by one or two resting cycles. Frequent blood samples were taken to monitor the endocrine response. Treatment with hCG alone or with the various combinations of RU 486 produced similar serum levels of oestradiol and progesterone which were equivalent to those observed during early pregnancy. With hCG alone, the onset of bleeding was on day 21-24 after the LH surge, coinciding with the drop in oestradiol and progesterone. With RU 486 doses of 50 mg/day or more, an early bleeding episode almost invariably occurred on day 14-17 after the LH surge in the presence of high circulating steroid levels. In contrast, 25 mg/day RU 486 for 4 days failed to induce this early onset of bleeding in three out of six cases.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: When administered during the luteal phase of the menstrual period, human chorionic gonadotropin (hCG) has been observed to induce a pseudopregnancy in which the functional lifespan of the corpus luteum is prolonged. On the assumption that women with hCG-induced prolongation of the luteal phase offer an ideal model for studying the in vivo action of RU-486 and other antiprogestins, 23 women (5 of whom were IUD users) were administered hCG alone. hCG, and RU-486, tamoxifen, or both RU-486 and tamoxifen. Increasing doses of hCG produced a progressive rise in estradiol and progesterone to levels compatible with early pregnancy; steroid levels declined after cessation of hCG treatment and bleeding occurred 21-24 days after the midcycle luteinizing hormone (LH) surge. This indicates that the luteal phase was prolonged by at least 8 days. RU-486 doses of 50 mg/day and above produced bleeding 14-17 days after the LH surge in the presence of high levels of circulating steroids, while a 25 mg dose of RU-486 failed to produce bleeding in 50% of cases and tamoxifen failed to induce early bleeding or to potentiate the effect of RU-486 at either dose. A 2nd bleeding episode occurred 22-24 days after the LH surge coincident with a drop in circulating steroids in 43% of cycles; a 2nd bleeding episode was significantly correlated with a lower total dose (200 and 400 mg) of RU-486. Endometrial biopsies in those with late bleeding showed a mixed proliferative and secretory pattern indicative of incomplete shedding. A total dose of 700 or 800 mg of RU-486 is recommended to produce complete shedding.

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Ectopic implantation of the embryo in the tube opposite to the ovary containing the corpus luteum constitutes evidence of peritoneal or uterine transmigration of the egg. The frequency of this phenomenon was reinvestigated utilizing histopathologic confirmation of the side of the corpus luteum. A tubal pregnancy contralateral to the ovulating ovary was found in 28% of 67 cases, indicating that either the oocyte, the zygote or the embryo had entered the tube in which implantation took place from a medial site such as the peritoneal or the uterine cavity rather than directly from the ovulating ovary. Assuming that once in the medial site there is equal chance of entering either tube, it follows that in 56% of tubal pregnancies the egg has entered the tube from a midline location. Attempts to recover the oocyte from the tubes in normal women were successful in fewer than 5% of cases contralateral to the corpus luteum. It is concluded that tubal pregnancy is associated with a significant increase in the occurrence of transmigration of the egg.

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