1 Pedriatric and Reproductive Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Building 10 Room 9D42, 10 Center Dr. MSC 1583, Bethesda, MD 208921583, 2 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, George Washington University Medical Center, Washington DC, 3 Department of Nursing, Warren Grant Magnusen Clinical Center, 4 Surgical Pathology, National Cancer Institute, National Institutes of Health, and 5 Division of Epidemiology, Statistics, and Prevention, National Institute of Child Health and Human Development, Bethesda, MD 208921583, USA
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: antiprogestin/CDB-2914/endometrium/follicle
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Follicular phase administration of mifepristone blocks or delays ovulation in a dose-dependent fashion. At doses of 110 mg, ovulation is delayed but not abolished (Spitz et al., 1993). At higher doses, 200600 mg, a new follicle is often recruited (Liu et al., 1987
; Shoupe et al., 1987
), so that a single 600 mg dose is more likely to cause a 1 week delay in menses (36%) than 10 mg (18%) (World Health Organization, 1999
).
The threshold minimal dose of antiprogestin that alters endometrial maturation is lower than that for ovarian effects (Danielsson et al., 1997). Batista et al. demonstrated a delay in luteal phase maturation with mifepristone 1 mg daily, but minimal effects on ovulation (Batista et al., 1992a
). Interestingly, although endometrial maturation has been extensively investigated after luteal phase administration (Greene et al., 1992
; Gemzell-Danielsson et al., 1994
; Cameron et al., 1997
) it has not been examined after follicular phase use.
CDB-2914, a new agent with antiprogesterone and antiglucocorticoid activity, was developed by the National Institute of Child Health and Human Development (NICHD). As shown in Figure 1, CDB-2914 is a synthetic steroid analogue with structural similarity to progesterone and mifepristone. In a phase I safety and toxicity study of a single mid-luteal dose (placebo, 1, 10, 50, 100 and 200 mg) in normally cycling women, no adverse events or antiglucocorticoid activity were noted (Passaro et al., 1997
). The compound and its metabolites, as detected by radioimmunoassay, have a terminal elimination half-life of 12136 h (L.Nieman, personal communication). Early menses consistently occurred at the highest dose, demonstrating antiprogestational activity.
|
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Preparation of CDB-2914
Pure crystalline CDB-2914 was synthesized by Southwest Foundation for Biomedical Research (San Antonio, TX, USA). The Clinical Center Pharmaceutical Development Service sieved CDB-2914 and formulated 10, 50 and 100 mg doses of active agent, or inert material (placebo) in gelatin capsules. Initially, only the placebo, 10, and 50 mg dose were studied and randomization was done in three blocks of six and one block of three for a total sample size of 21. A 100 mg dose was added, at the time when data from the phase I study were available. Randomization for the next 24 subjects occurred in one block, assigning most to the 100 mg dose and some to each of the other three doses to achieve a total sample size of 45 and to ensure that at least 10 women in each dose group completed the study. The final dose groups each included 1012 women (placebo or 10 mg, n = 12; 50 mg, n = 11; and 100 mg, n = 10). Investigators and subjects were not aware of the dose or agent administered.
Study design
Women participated in the study for three consecutive menstrual cycles (Figure 2). The first and third were intended to document menstrual cycle length and ovulation, while the second was the treatment cycle. At study entry, each woman was instructed in the use of an in home urinary LH kit, menstrual calendar, coital log and basal body temperature chart to be completed for all three cycles. Urinary LH was measured using a self-test or one-step test (OvuQUICKTM; Quidel, San Diego, CA, USA); each assay had a threshold of 40 mIU/ml and identified the LH surge on the same day as radioimmunoassay 98% of the time (Quidel, unpublished data) and on the same day as enzyme immunoassay 96% of the time (Elkind-Hirsch et al., 1986
). In the first cycle, a plasma progesterone concentration was measured 1 week after the reported urine LH surge. Women progressed to the treatment cycle if the first cycle was ovulatory, with normal follicular maturation, and had normal length. Menstrual cycle length was considered normal if it was in the range 2435 days with a luteal phase at least 12 days in length. A menstrual cycle was defined as ovulatory if the mid-luteal plasma progesterone measurement was >4 ng/ml.
|
Women received CDB-2914 or placebo when the lead follicle was 1416 mm in diameter. Subsequently, blood for oestradiol and progesterone, and a transvaginal sonogram were obtained daily until follicular collapse. To evaluate the safety of CDB-2914, blood chemistries, a complete blood count, and hepatic panel were obtained 57 days after dosing.
Women reported whether the LH kit was positive at the daily visit. To confirm the urine LH kit results, plasma LH was measured retrospectively by radioimmunoassay on the days of each reported positive urinary LH test as well as the day before and after. Any plasma LH value of >30 mIU/ml was considered to indicate an LH surge.
At 57 days after follicular collapse by ultrasound, an endometrial biopsy was performed, transvaginal sonography was done to determine the presence of ovarian cysts, and blood was obtained for measurement of oestradiol and progesterone. On the sonographic examination, an echolucent, cystic structure measuring >15 mm in diameter was considered to be an ovarian cyst. Because a change in lead follicle had been observed in some subjects, ovarian cysts noted in the luteal phase were followed as an additional evaluation of toxicity. When an ovarian cyst was noted, a limited pelvic vaginal sonogram, and blood oestradiol and progesterone measurements were repeated in the early follicular and mid-luteal phase in each subsequent cycle until the cyst resolved. Endometrial biopsies were performed using a Pipelle endometrial suction curette (Unimar, Wilton, CT, USA) and placed in neutral buffered formalin.
The third cycle was included to document any post-treatment effects on ovulation and menstrual cycle length. Ovulation was assessed by serum progesterone measured 7 days after a reported positive urine LH test. If the menstrual cycle was of abnormal length (<24 or >35 days) or the progesterone was <4 ng/ml, the woman was observed for another menstrual cycle.
Hormone assays and analysis
Blood samples were centrifuged and plasma was stored at 20°C until assayed. A radioimmunoassay was used to quantify concentration of oestradiol (Jiang and Ryan, 1969; Abraham et al., 1972
), progesterone (DeVilla et al., 1972
), and LH (Odell et al., 1967
). LH values are expressed in terms of the Second International Reference Preparation for human menopausal gonadotrophin (HMG). The intra-assay coefficient of variation was
10%, and the inter-assay coefficient of variation was
15%. The maximal plasma oestradiol concentration in the 4 days after dose and in the 4 days before follicular collapse was noted. The cumulative oestradiol concentration after dose until ovulation was calculated as the sum of the daily measurements during this time period.
Endometrial biopsies
After routine haematoxylin and eosin staining, one pathologist (M.M.), unaware of treatment, assigned a post-ovulatory date for the specimen using the evaluation criteria of Noyes (Noyes et al., 1950) giving a 2 day spread. Biopsies were considered to be abnormal if there were >2 days delay in the pathological date compared with the chronological day of cycle based on the next menses.
Cycle phase lengths
A menstrual cycle was the number of days from the first day of menses to the beginning of the next menses. The follicular phase included the first day of menses to the day of the positive urine LH test. The luteal phase was defined as the day after the reported urinary LH surge until the next menses. In the treatment cycle, the number of days from the urinary LH surge until follicular collapse was calculated. The time interval from the day of treatment to follicular collapse was also determined.
Statistical analyses
A sample size of 50 women was sought to have at least 40 completing the study. The hypothesis tested was that CDB-2914 would delay ovulation so that 90% of women in the placebo group would ovulate within 6 days of dosing, compared with 10% at the highest dose. The other two dose groups would have a probability of a collapsed follicle within 6 days of 1090%. A sample size of 40 would give the study 90% power to detect an absolute difference between 90% in the placebo group and 10% at 100 mg at the 0.05 level with a two-sided test. The frequency of adverse events, ovarian cysts, and laboratory abnormalities was determined to evaluate the safety of the drug.
Baseline characteristics among the dose groups were compared using analysis of variance (ANOVA). The treatment menstrual cycle parameters were compared with baseline and post-treatment cycles and ANOVA. Doseresponse trends among treatment groups were assessed by ANOVA, JonckeheereTerpstra, or KruskalWallis for continuous variables, e.g. oestradiol concentration, follicular diameter, and the relationship between oestradiol concentration and follicular diameter, and by 2 or CochranArmitage for discrete variables such as altered endometrial maturation and presence of luteinized unruptured follicles. Values are expressed as mean ± SE. P < 0.05 in a two-sided test was considered to be statistically significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The mean age of the 44 women included in the analysis was 33 years (range 2142). Twenty-two were Caucasian, 18 were Black, two were Hispanic and two were Asian. Of the 28 who had been pregnant, 25 had children and three had therapeutic abortions. The mean body mass index was 24.2 kg/m2; range 17.428.5 kg/m2. There was no significant difference in race, age, follicle number at baseline, body mass index, gravidity, and parity among any of the treatment groups.
Follicle number and growth
Women aged <30 years had more follicles on the day of dosing than those aged >40 years (16 ± 1.1 versus 9 ± 2.0 follicles; P = 0.0006). Between two and six women in each treatment group had more than one follicle measuring >10 mm on the day of dose (P = 0.3).
CDB-2914 suppressed growth of the lead follicle during the 4 days after treatment (P < 0.001) (Figure 3). Sometimes the stunted follicle would resume growth after a few days; at other times, the initial lead follicle stopped growing and was replaced by a new lead follicle. Five women, one each at placebo, 10 mg and 50 mg, and two at 100 mg, had at least two lead follicles on the day of dosing, one of which remained the lead follicle. CDB-2914 caused a dose-dependent change to a new lead follicle for 11 women: one at placebo, two at 10 mg, three at 50 mg, and five at 100 mg had a change in lead follicle (P < 0.03 for trend) (Table I
). One woman, in the 50 mg dose group, developed two lead follicles that grew to >20 mm. After dosing, the first lead follicle had little growth for a week, but then grew to 45 mm diameter. The second lead follicle emerged 1 week after dosing, grew to 22.8 mm and then collapsed 18 days after dosing.
|
|
The rate of lead follicle growth during the 4 days before follicular collapse was similar in all groups, although the maximal lead follicular diameter was greater at 100 mg of CDB-2914 (Figure 4). Three women who had a sonographic pattern consistent with luteinized unruptured follicles had the largest observed follicular diameters and accounted for the significant difference (P < 0.01) in maximal diameter observed between women receiving 100 mg and those receiving other doses. The finding of luteinized unruptured follicles in three of the 10 women who received 100 mg of CDB-2914, was significantly different from the absence of luteinized unruptured follicles in all other groups (P < 0.01;
2 test). Progesterone concentrations of those with luteinized unruptured follicles rose to luteal phase concentrations after the LH surge, before the follicle was completely filled in, suggesting early luteinization of the follicle.
|
|
|
|
|
Ovarian cysts noted at endometrial biopsy
Asymptomatic luteal phase cysts were noted at the time of endometrial biopsy for two women at placebo, four at 50 mg and four at 100 mg CDB-2914 (Table II). Women who developed a new lead follicle were not more likely to have luteal phase cysts. The cyst size was independent of treatment and measured 1523 mm in five women and 2933 mm in five others. Cysts spontaneously resolved within 2 months of treatment in nine of the 10 women. The remaining subject had a 16 mm cyst that persisted through 3 months of follow-up.
|
Effects on cycle length
There was no significant difference among the treatment groups in the baseline or post-treatment menstrual cycle parameters, including the follicular or luteal phase (data not shown), or overall cycle lengths (Table III). The 50 and 100 mg dose groups had treatment cycles that were, on average, 4 days longer than the placebo or 10 mg dose groups (P < 0.01). The treatment cycle was lengthened by 12 weeks in 30% at 100, 27% at 50 and 9% at 10 mg. This increase was due to a 1 week delay in menses observed only in eight of the 10 CDB-2914 treated women with a change in lead follicle (one at 10 mg, three at 50 mg, and four at 100 mg) (P < 0.02 for trend).
|
Ovulation data in the cycle following CDB-2914 administration were available for all but two women. For those with a progesterone concentration <4 ng/ml after a reported LH surge, a biphasic pattern on the basal body temperature was considered to indicate ovulation. In all, 35 out of 42 women had ovulatory cycles. Of the other seven women, three were in the placebo group, three at 50 mg and one at 100 mg, including two who also had an abnormal cycle length (cycle length 42 and 17 days). All of these women had an ovulatory cycle in the second cycle after treatment.
Safety of CDB-2914
CDB-2914 was well tolerated at all doses. All post-treatment laboratory values were normal. Two women had gastrointestinal or flu symptoms from intercurrent illness, and one, with a history of migraines, had a migraine within 2 days of dosing. Four women (three at 100 mg and one at 50 mg) reported lower abdominal pain with the collapse of the 3051 mm follicles.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A single mid-follicular dose of CDB-2914 impeded folliculogenesis, causing a dose-dependent delay in time to ovulation and diminished oestradiol secretion. After CDB-2914, follicular growth was initially stunted and then resumed a normal linear rate of growth to reach a maximal diameter similar to placebo. Despite regaining a normal follicular growth pattern, daily steroidogenesis was diminished at all doses. Liu and colleagues reported similar reductions in oestradiol when RU-486 was given at a dose of 3 mg/kg, orally, once daily for 3 days when the dominant follicle was 1.52.0 cm in diameter (Liu et al., 1987).
The mechanism(s) by which CDB-2914 exerts these profound effects on follicular growth and maturation is unclear. One possibility is that, at higher doses, initial inhibition of lead follicle growth was irreversible. The ability of a second smaller follicle to continue growing, become the subsequent lead follicle and ultimately ovulate, suggests that the effects of CDB-2914 may be most detrimental to larger follicles. Such a putative action on developmentally vulnerable follicles is consistent with either a direct ovarian effect, or an alteration in gonadotrophin pulse patterns or concentrations. It is tempting to speculate that the CDB-2914 may inhibit the action of the progesterone receptor or oestrogen receptor ß, both of which were recently described as abundant in granulosa cells of developing follicles (Revelli et al., 1996; Enmark et al., 1997
). As frequent FSH and LH concentrations were not measured in this study, we cannot distinguish between these possibilities. Other antiprogestins are known to influence LH pulsatility, however, and this may explain the demise of the gonadotrophin-dependent dominant follicle (Permezel et al., 1989
). A change in LH pulsatility, amplitude and mean serum LH were not observed on the third day of a mid-follicular dose of mifepristone in a study by Liu (Liu et al., 1987
).
The increase in time between the LH surge and follicular collapse, and the unusual observation of two LH surges also must be integrated into a model of CDB-2914 action. In the latter case, an initial LH surge failed to initiate collapse of follicles 1420 mm in diameter. We speculate that this represents either an inappropriately early LH surge, or an inhibition of the ovarian cascade that normally initiates follicle rupture. The observation of luteinized unruptured follicles may, in a similar way, represent a failure of the follicle to signal readiness for ovulation. The present results are similar to previous reports (Liu et al., 1987; Shoupe et al., 1987
; Batista et al., 1994
). that treatment of normal women with mifepristone during different stages of the follicular phase postpones the mid-cycle LH surge and delays ovulation. We previously reported the effects of mid-follicular administration of low dose mifepristone (1 mg daily for 5 days) in women with hypothalamic amenorrhoea undergoing ovulation induction with gonadotrophin-releasing hormone (GnRH) pulses (Batista et al., 1994
). In that study, while follicular growth rate was not altered, an increase in the time to ovulation was associated with increased maximal follicular diameter compared with the placebo. In this study, where GnRH pulses were not held constant, lengthening of the time interval from LH surge to collapse may be similar to the blocking or attenuation of the mid-cycle LH surge observed by others after mifepristone. Shoupe et al. observed an attenuated LH surge with a lower peak LH than in the control cycles after 50 mg of mifepristone given twice a day on days 1017 of the cycle (Shoupe et al., 1987
). After 3 mg/kg of mifepristone was administered daily for three days in the mid-follicular phase by Liu, a delayed LH surge with a higher peak LH was observed during the treatment cycle when compared to the control cycle (Liu et al., 1987
).
The initial inhibition of oestradiol concentrations during the 4 days after CDB-2914 is consistent with the inhibition of follicular growth; the normal positive correlation between increasing follicle diameter, granulosa cell mass, and steroidogenesis was preserved at placebo and 10 mg. We infer that the lack of follicular growth at 50 and 100 mg represents failure of granulosa proliferation and that the apparent decrease in oestradiol concentrations relative to placebo reflects this diminished granulosa cell volume. By contrast, diminished oestradiol concentration was related to the increasing follicle diameter in the 4 days before follicle collapse at any dose of CDB-2914, suggesting that the proliferative capacity was less impaired than the steroidogenic capacity. In addition, daily oestradiol concentrations were decreased, especially at the higher doses. It is unclear whether these lower oestradiol concentrations might cause any adverse effects or could be exploited for the treatment of other conditions, like endometriosis.
Those with a delay in ovulation after CDB-2914 had a longer treatment cycle. This is similar to the dose-dependent effect seen with mifepristone (World Health Organization, 1999). Any effect on menstrual cycle length was limited to the treatment cycle, returning to a normal length within one cycle. Post-treatment cycle abnormalities of anovulation or abnormal cycle length were uncommon and occurred at a similar rate in all groups. No women experienced breakthrough or prolonged bleeding after treatment, and the agent appeared to be safe and well tolerated when given in this way.
In conclusion, follicular phase CDB-2914 at single doses significantly delays endometrial maturation and diminishes oestradiol concentrations with minimal effects on the menstrual cycle. The good safety profile shown here allows for further exploration of the potential clinical utility of CDB-2914 for emergency contraception and the treatment of endometriosis.
![]() |
Acknowledgments |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Batista, M.C., Cartledge, T.P., Zellmer, A.W. et al. (1992a) Delayed endometrial maturation induced by daily administration of the antiprogestin RU 486: a potential new contraceptive strategy. Am. J. Obstet. Gynecol., 167, 6065.[ISI][Medline]
Batista, M.C., Cartledge, T.P., Zellmer, A.W. et al. (1992b) Evidence for a critical role of progesterone in the regulation of the midcycle gonadotropin surge and ovulation. J. Clin. Endocrinol. Metab., 74, 565570.[Abstract]
Batista, M.C., Cartledge, T.P., Zellmer, A.W. et al. (1994) The antiprogestin RU486 delays the midcycle gonadotropin surge and ovulation in gonadotropin-releasing hormone-induced cycles. Fertil. Steril., 62, 2834.[ISI][Medline]
Brenner, R.M. and Slayden, O.D. (1994) Oestrogen action in the endometrium and oviduct of rhesus monkeys during RU486 treatment. Hum. Reprod., 9 (Suppl. 1), 8297.[ISI][Medline]
Bygdeman, M., Danielsson, K.G. and Swahn, M.L. (1997) The possible use of antiprogestins for contraception. Acta Obstet. Gynecol. Scand., 164 (Suppl.), 7577.
Cameron, S.T., Critchley, H.O., Buckley, C.H. et al. (1997) Effect of two antiprogestins (mifepristone and onapristone) on endometrial factors of potential importance for implantation. Fertil. Steril., 67, 10461053.[ISI][Medline]
Danielsson, K.G., Swahn, M.L., Westlund, P. et al. (1997) Effect of low daily doses of mifepristone on ovarian function and endometrial development. Hum. Reprod., 12, 124131.[ISI][Medline]
DeVilla, G.O., Jr, Roberts, K., Wiest, W.G. et al. (1972) A specific radioimmunoassay of plasma progesterone. J. Clin. Endocrinol. Metab., 35, 458460.[ISI][Medline]
Elkind-Hirsch, K., Goldzieher, J.W., Gibbons, W.E. and Besch, P.K. (1986) Evaluation of the OvuSTICK urinary luteinizing hormone kit in normal and stimulated menstrual cycles. Obstet. Gynecol., 67, 450453.[Abstract]
Enmark, E., Pelto-Huikko, M., Grandien, K. et al. (1997) Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. J. Clin. Endocrinol. Metab., 82, 42584265.
Gemzell-Danielsson, K., Svalander, P., Swahn, M.L. et al. (1994) Effects of a single post-ovulatory dose of RU486 on endometrial maturation in the implantation phase. Hum. Reprod., 9, 23982404.[Abstract]
Glasier, A., Thong, K.J., Dewar, M. et al. (1992) Mifepristone (RU 486) compared with high-dose estrogen and progestogen for emergency postcoital contraception. N. Engl J. Med., 327, 10411044.[Abstract]
Greene, K.E., Kettel, L.M. and Yen, S.S. (1992) Interruption of endometrial maturation without hormonal changes by an antiprogesterone during the first half of luteal phase of the menstrual cycle: a contraceptive potential. Fertil. Steril., 58, 338343.[ISI][Medline]
Gronemeyer, H., Benhamou, B., Berry, M. et al. (1992) Mechanisms of antihormone action. J. Steroid Biochem. Mol. Biol., 41, 217221.[ISI][Medline]
Jiang, N.S. and Ryan, R.J. (1969) Radioimmunoassay for estrogens: a preliminary communication. Mayo Clin. Proc., 44, 461465.[ISI][Medline]
Kettel, L.M., Murphy, A.A., Morales, A.J. and Yen, S.S. (1994) Clinical efficacy of the antiprogesterone RU486 in the treatment of endometriosis and uterine fibroids. Hum. Reprod., 1, 116120.
Liu, J.H., Garzo, G., Morris, S. et al. (1987) Disruption of follicular maturation and delay of ovulation after administration of the antiprogesterone RU486. J. Clin. Endocrinol. Metab., 65, 11351140.[Abstract]
McDonnell, D.P., Shahbaz, M.M., Vegeto, E. and Goldman, M.E. (1994) The human progesterone receptor A-form functions as a transcriptional modulator of mineralocorticoid receptor transcriptional activity. J. Steroid Biochem. Mol. Biol., 48, 425432.[ISI][Medline]
Murphy, A.A. and Castellano, P.Z. (1994) RU486: pharmacology and potential use in the treatment of endometriosis and leiomyomata uteri. Curr. Opin. Obstet. Gynecol., 6, 269278.[ISI][Medline]
Nieman, L.K., Choate, T.M., Chrousos, G.P. et al. (1987) The progesterone antagonist RU 486: A potential new contraceptive agent. N. Engl. J. Med., 316, 187191.[Abstract]
Noyes, R.W., Hertig, A.T. and Rock, J. (1950) Dating the endometrial biopsy. Fertil. Steril., 1, 325.[ISI][Medline]
Odell, W.D., Rayford, P.L. and Ross, G.T. (1967) Simplified, partially automated method for radioimmunoassay of human thyroid-stimulating, growth, luteinizing, and follicle stimulating hormones. J. Lab. Clin. Med., 70, 973980.[ISI][Medline]
Passaro, M., Piquion, J., Mullen, N. et al. (1997) Safety and luteal phase effects of the antiprogestin CDB-2914 in normally cycling women. In Proceedings of the 79th meeting of the Endocrine Society. Endocrine Society, Minneapolis, MN, USA.
Permezel, J.M., Lenton, E.A., Roberts, I. and Cooke, I.D. (1989) Acute effects of progesterone and the antiprogestin RU 486 on gonadotropin secretion in the follicular phase of the menstrual cycle. J. Clin. Endocrinol. Metab., 68, 960965.[Abstract]
Queenan, J.T., O'Brien, G.D., Bains, L.M. et al. (1980) Ultrasound scanning of ovaries to detect ovulation in women. Fertil. Steril., 34, 99105.[ISI][Medline]
Revelli, A., Pacchioni, D., Cassoni, P. et al. (1996) In situ hybridization study of messenger RNA for estrogen receptor and immunohistochemical detection of estrogen and progesterone receptors in the human ovary. Gynecol. Endocrinol., 10, 177186.[ISI][Medline]
Shoupe, D., Mishell, D.R., Jr, Page, M.A. et al. (1987) Effects of the antiprogesterone RU 486 in normal women. II. Administration in the late follicular phase. Am. J. Obstet. Gynecol., 157, 14211426.[ISI][Medline]
Spitz, I.M., Croxatto, H.B., Salvatierra, A.M. and Heikinheimo, O. (1993) Response to intermittent RU486 in women. Fertil. Steril., 59, 971975.[ISI][Medline]
World Health Organization (1999) Comparison of three single doses of mifepristone as emergency contraception: a randomised trial. Task Force on Postovulatory Methods of Fertility Regulation. Lancet, 353, 697702.[ISI][Medline]
Submitted on August 11, 1999; accepted on January 31, 2000.