1 TAP Pharmaceutical Products Inc., Lake Forest, IL, USA and 2 EnTec GmbH, Jena, Germany. 3 Current address: Schorlemerallee 12B, 14195 Berlin-Dahlem, Germany
4 To whom correspondence should be addressed at: TAP Pharmaceutical Products Inc., 675 N. Field Drive, Lake Forest, IL 60045, USA. Email: kristof.chwalisz{at}tap.com
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: asoprisnil/amenorrhea/endometrium/menstrual cycle prolongation/selective progesterone receptor modulator
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
PR-mediated responses were studied in different animal models, including rabbits, guinea pigs and non-human primates (Chwalisz et al., 2000; Elger et al., 2000
; DeManno et al., 2003
). In the rabbit endometrium, both asoprisnil and J912 exhibited partial (mixed) agonist and antagonistic effects, depending on the absence or presence of progesterone (Elger et al., 2000
; DeManno et al., 2003
). Partial PR agonist/antagonist effects were also observed in cycling and ovariectomized guinea pigs (DeManno et al., 2003
). Unlike classical progesterone antagonists (PAs), mifepristone and onapristone, asoprisnil showed only marginal labour-inducing activity during mid-pregnancy and was completely ineffective in inducing preterm parturition in the guinea pig (Elger et al., 2000
; DeManno et al., 2003
). This is most likely due to the presence of its intrinsic progesterone agonistic activity. In non-human primates, asoprisnil at high doses completely eliminated menstrual cyclicity and induced endometrial atrophy in the presence of follicular phase estradiol (E2) concentrations (DeManno et al., 2003
). These studies also demonstrated tissue-selective effects of asoprisnil, with the endometrium as the preferred target.
This double-blind, dose-escalation study evaluated the effects of asoprisnil on menstrual and ovarian cyclicity, and safety parameters in normal premenopausal women during 1-month oral administration.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
All enrolled women had to agree to use double barrier contraception (condom, sponge, or diaphragm, with spermicidal foam or jelly) throughout the study and until the onset of the first post-treatment menstrual period unless surgically sterilized. The study was conducted at two independent Phase I clinical research study sites. The study was performed according to the ethical principles of the Declaration of Helsinki (1989 revision). The Institutional Review Board (IRB) at each of these sites approved the protocol, and each woman signed the IRB-approved written informed consent prior to the screening evaluation. The study was conducted between January 1999 and March 2000.
Study design
This was a Phase I, randomized, double-blind, placebo-controlled, dose-escalation study of asoprisnil administered for 28 days. Asoprisnil or placebo capsules were administered orally starting during the first 4 days of the menstrual cycle. The study included six dose groups: 5 mg once daily (QD), 5 mg twice daily (BID), 10 mg QD, 25 mg QD, 25 mg BID and 50 mg BID. Each dose group consisted of 10 women, eight of whom received asoprisnil whereas the remaining two received placebo. The effect of asoprisnil on cycle length was the primary pharmacodynamic outcome of this study. Various endocrine parameters, endometrial biopsy results, and endometrial thickness were considered as secondary pharmacodynamic outcomes.
Asoprisnil capsules were supplied in doses of 5 mg and 25 mg. The placebo capsules were indistinguishable from those of asoprisnil. Upon successful enrollment, women within each dose group were sequentially assigned subject numbers that encoded the random assignment of the woman, via a randomization schedule, to one of the treatments (i.e. asoprisnil or placebo). Study drug was supplied to the site packaged in sealed kits that contained the appropriate number of bottles of asoprisnil or placebo.
Doses were taken in the morning after fasting; the second dose of the BID doses was taken in the evening 12 h after the first dose. The women were confined to the testing facility for two intervals. The first confinement began on Day 1. The initial dose was administered on the following day (Day 1); and the women were discharged on the morning of the next day (Day 2). The women returned to the testing facility on Day 5 and then every three days for study drug dispensing, clinical evaluation, safety assessment and blood sampling. The second confinement began on Day 27 and continued until discharge on Day 30. With all dose schedules, the last dose was taken on the morning of Day 28.
A baseline transvaginal ultrasound was performed during the pretreatment cycle on Day 21, repeated during the treatment period on the same menstrual cycle day, and once again during the post-treatment period on Day 37 if menses had not occurred. The occurrence of ovarian cysts >3 cm was assessed at each transvaginal ultrasound examination. An endometrial biopsy was performed using a Pipelle (R) catheter on the same day of the treatment cycle as the ultrasound. Initially, it was proposed to interpret the endometrial biopsy on the basis of the Noyes criteria (Noyes, et al., 1950). However, because of mixed progesterone agonist/antagonist effects of asoprisnil on the endometrium, leading to asynchronous differentiation of endometrial epithelium and stroma, the biopsy results could not be interpreted on this basis. Instead, the biopsies were reanalyzed according to a new classification system developed by TAP Pharmaceutical Products Inc., Lake Forest, IL, Diagnostic Cytology Laboratories, Indianapolis, IN, and an expert panel of gynecological pathologists. This new classification, which was based on Blaustein's Pathology of the Female Genital Tract (Kurman and Mazur, 1994; Kurman and Norris, 1994
), included two new categories describing specific effects of asoprisnil on the endometrium. The first category, non-physiologic secretory effects, is characterized by weak secretory effects on endometrial glands without any mitotic figures and variable effects on endometrial stroma ranging from stromal compaction to focal predecidual changes. The second category, secretory pattern, mixed type, differs from the first category by the presence of isolated mitotic figures in endometrial glands.
Menstrual diaries
Each woman completed a daily diary throughout the study in which she recorded any uterine bleeding, the time of study drug administration, and any adverse events. The staff reviewed this diary at each clinic visit.
Hormonal analyses
LH, E2, estrone (E1) and progesterone were measured on Days 1, 5, 14, 17, 23 and 28; FSH, prolactin, free testosterone (fT), and sex hormone-binding globulin (SHBG) were measured on Days 1, 14 and 28. Blood collections for cortisol (C) and dehydroepiandrosterone sulphate (DHEA-S) determination were taken at 7 am on Days 1, 5, 11, 17, 23, 28 and 29; cortisol was also measured at 8 pm on Days 1, 28 and 29. All hormonal assay analyses were conducted at Esoterix Inc. (former Endocrine Sciences, Calabasas Hills, CA), who developed all hormonal assays used in this study.
FSH, LH and prolactin were determined by an immunochemiluminometric assay developed by Esoterix Inc. This method utilizes paired monoclonal antibodies to provide highly sensitive and specific measurements. SHBG was assayed by a highly sensitive immunoradiometric assay. The intra-assay and inter-assay precision of protein hormones and SHBG assays ranged from 4 to 8% [coefficient of variation, (%CV)], respectively.
E2 and E1 were measured by radioimmunassay (RIA) after extraction and LH20 column chromatography. Samples were extracted with hexane:ethyl acetate (80:20). The recovery of each sample, which was monitored by adding [3H]E2 before extraction, was 70%. Progesterone was measured by RIA after extraction with hexane:ethyl acetate (80:20) with a recovery >90%. C was measured directly in serum by RIA. A non-crossreactive steroid was used to displace C from cortisol binding globulin. Samples were diluted before assay to a concentration of C suitable for accurate measurement. DHEA-S was measured as DHEA by RIA after enzymolysis of the DHEA sulfate without extractions and chromatography. Total serum testosterone is measured by RIA after extraction with hexane:ethyl acetate (80:20) and column chromatography using Al2O3 micro-columns. Equilibrium dialysis was used to determine fT. Intra-assay variation of steroid hormone assays ranged from 26% and the inter-assay variation ranged from 217% depending on the hormone concentration. There was no cross-reactivity with asoprisnil and its metabolites in the E2, E1, C, DHEA and progesterone RIAs. However, there may have been cross-reactivity in the fT assay with asoprisnil or one of its metabolites as observed in subsequent studies. The assays used to measure total and free testosterone are currently being validated versus a more specific method (high-performance liquid chromatography, gas chromatography/mass spectrometry).
Safety parameters
Liver function was determined by total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, lactic dehydrogenase and alkaline phosphatase. Blood urea nitrogen and creatinine were evaluated to assess renal function. In addition, all women had complete blood counts, serum biochemical determinations including albumin, total protein, glucose, chloride, potassium, sodium, thyroid-stimulating hormone (TSH) and total thyroxin (total T4), as well as urinalysis. These tests were performed between 8 and 10 am during the screening visit, on Days 1, 5, 11, 17, 23 and 27 of the treatment period and on Day 30 during the post-treatment visit. Pregnancy testing was performed during screening and the visits on Day 1, 11, 20, 27 and 30. Clinical and safety assessments including monitoring for adverse events and use of concurrent medications, as well as vital signs and electrocardiogram (ECG), were frequently performed.
Data analysis and statistical methods
For all analyses, the results from the placebo subjects of the six dosing regimens were pooled, giving a total of 12 women who received placebo.
The effect of asoprisnil on the menstrual cycle was measured by comparing the cycle lengths for the different dosing regimens. Cycle length was defined as the number of days from the beginning of the woman's baseline menses during which dosing started to the first day of her next menses (during or after the 28 days of treatment). Mean cycle length was calculated for each dosing regimen and comparison was made using a one-way analysis of variance (ANOVA) with dosing regimen as the factor. For this and all following ANOVAs, pairwise comparisons to placebo, a comparison of 10 mg QD to 5 mg BID, and a test for linear effect of total daily dose were also made within the framework of the ANOVA model. All P-values <0.05 were regarded as significant unless otherwise specified.
Serum luteal phase progesterone concentrations during the treatment cycle were used to determine the presence of corpus luteum formation. The cycle was arbitrarily defined as indicative of luteinization if at least one progesterone measurement exceeded 3.5 ng/ml during treatment. These results were cross-tabulated by dosing regimen.
Intermenstrual bleeding was defined as bleeding between the end of the baseline menses and before the start of the next menses, excluding bleeding attributed to the endometrial biopsy. Mean and median number of days of intermenstrual bleeding was calculated for each dosing regimen and pairwise comparisons to placebo were made using a KruskalWallis test, as the data were not normally distributed.
Changes from baseline in hormone concentrations were calculated for each dosing regimen and analyzed for each treatment visit using separate one-way ANOVAs with dosing regimen as the factor. The seven pairwise comparisons at each visit (pairwise comparisons to placebo and a comparison of 10 mg QD to 5 mg BID) were assessed using Hochberg's multiple comparison procedure (Hochberg, 1988).
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
|
E2: Typical, cycle-dependent increases in E2 were observed for all doses of asoprisnil as well as placebo (Figure 4A and B). Although no statistically significant pairwise differences were evident, the highest asoprisnil dose (50 mg BID) was associated with lower E2 concentrations. There was a trend towards lower mean E2 concentrations mid-cycle (Day 17) (linear contrast P=0.01).
|
Progesterone: The patterns of progesterone concentrations at 5 mg QD (Figure 5A) were consistent with normal occurrence of corpus luteum formation and luteolysis. At higher asoprisnil doses (Figure 5B), the mean luteal phase progesterone increases were smaller as the asoprisnil dose increased (linear contrast at Day 17 P < 0.05) reflecting the lower rate of subjects with progesterone levels indicative of luteinization (Figure 5B). In those asoprisnil-treated women who showed luteal phase progesterone levels, the duration of the luteal phase seemed to be normal.
|
|
fT: There was a dose-dependent increase in fT on Days 14 and 28 (linear contrast P 0.05 at both time points). This data is not presented because of potential cross-reactivity of antibodies used to measure testosterone.
SHBG: A slight mean increase was observed at Day 14 in the placebo group. In contrast, decreases from baseline at Days 14 and 28 were observed for all dose regimens of asoprisnil, and were significantly different from placebo (Figure 7) except with the doses of 5 mg BID and 10 mg QD (Day 28). A dose effect was apparent on Days 14 and 28 (linear contrast P 0.01 at both time points).
|
Other effects
Intermenstrual bleeding: With the exception of the 25 mg BID dose group, little intermenstrual bleeding was reported. However, in the 25 mg BID dose group, five women reported bleeding and in one, this persisted intermittently for 15 days.
Endometrial thickness: Although slight mean decreases in endometrial thickness were observed with all asoprisnil doses, particularly in those women who received the highest doses, none of the changes were significantly different from placebo (data not shown).
Ovarian cysts: None of the women developed cysts >5 cm in diameter. One woman in the 10 mg QD group, one in the 25 mg QD group, and two women who received placebo had cysts measuring from 3.1 to 4.4 cm during the treatment phase. All of these were asymptomatic, and either disappeared or regressed to <3 cm at the follow up visit.
Endometrial biopsy
In the placebo group, seven of the 12 women showed normal secretory phase endometrium, three were classified as proliferative, and the remaining two showed non-physiologic secretory effects. A total of 47 biopsies were available for histological analysis in women treated with asoprisnil. The endometrial biopsies were consistent with partial (mixed) progesterone agonist/antagonist activity of asoprisnil. Twelve women (25%) demonstrated non-physiologic secretory effects. This was characterized by weak to moderate secretory activity in the glands with no mitotic figures. Another 12 (25%) women had endometrial histology classified as secretory pattern, mixed type. This was characterized by weakly proliferative and secretory glands with infrequent mitotic figures. In both categories, the endometrial stroma was either compact or showed non-uniform edema. Clusters of unusual thick-walled arterial vessels were occasionally observed. Another eight women showed a normal luteal phase endometrium. Five women demonstrated weak proliferative endometrium and another four an active proliferative endometrium. Finally, inactive or atrophic endometrium was observed in six women. No woman showed endometrial hyperplasia. In the asoprisnil groups, the non-physiologic secretory patterns (non-physiologic secretory effects and secretory pattern, mixed type) were evident at doses equal to and higher than 5 mg BID and 10 mg QD. There was no clear correlation between the frequency of these effects and asoprisnil dose. In asoprisnil groups, there were also no clear differences in endometrial morphology between biopsies obtained during anovulatory cycles and those indicative of luteinization. Figure 8 presents representative endometrial biopsy appearances observed after asoprisnil treatment for 28 days.
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Since treatment was commenced at the beginning of the cycle, the changes in hormonal patterns in the placebo-treated cycle characterized by a fall in FSH, mid-cycle increase in LH, increase in E2 with a less prominent increase in E1, as well as the elevation of progesterone during the luteal phase, were expected. Asoprisnil did not appear to have a meaningful effect on LH, FSH, prolactin, E2 and E1 concentrations, with the exception of LH patterns in high-dose (25 mg daily or greater) asoprisnil groups which showed an increase versus placebo during the late luteal phase. The interpretation of LH increase at high asoprisnil doses is difficult due to low frequency of blood sampling. Two possibilities should be taken into consideration: (i) an increase in basal LH concentrations during the luteal phase, and (ii) a delay in LH peak. Further studies will be needed to determine the mechanism of LH increase observed in high-dose asoprisnil groups.
There was also a suggestion that with the highest asoprisnil dose, E2 levels were slightly lower. This is compatible with the absence of corpus luteum formation, most likely due to anovulation, observed in this group of women. Thus, the cycle prolongation with asoprisnil occurs in the presence of early follicular phase levels of E2. In most of the asoprisnil-treated groups, mean progesterone levels were below that of the placebo, reflecting the absence of luteinization in some women, especially those who received the higher doses. It should be stressed that luteinization was defined in this study based on progesterone concentrations typical for the normal luteal phase. Hence, the presence of luteal phase progesterone may be indicative of either ovulation or luteinized unruptured follicle. Serial ultrasound examinations of the dominant follicle and frequent measurement of ovarian and pituitary hormones will be needed to determine the effects of asoprisnil on ovulation.
Suppression of menstruation irrespective of the effects on luteinization and progesterone withdrawal is a surprising finding that, to our knowledge, has not been previously described with any known pharmacological agent. Continuous administration of oral contraceptives or high-dose progestins is accompanied by amenorrhea, but both regimens consistently produce anovulation (Lobo and Stanczyk, 1994). Moreover, these treatments are associated with breakthrough bleeding and spotting. Similarly, amenorrhea induced by GnRH agonists or antagonists is due to the complete inhibition of ovarian hormonal activity and to anovulation (Conn and Crowley, 1991
). Continuous administration of the progesterone antagonist mifepristone also suppresses menstrual cyclicity at daily doses of 2 mg and 5 mg (Brown et al., 2002
) and more consistently at higher doses of 50 or 100 mg per day (Kettel et al., 1994
). Similarly, the progesterone antagonist onapristone administered in doses of 15 or 50 mg daily for 7 days in the follicular phase also prolongs the cycle, although a dose of 5 mg produced inconsistent effects (Croxatto et al., 1994
). However, there are fundamental differences between the effect of asoprisnil and both mifepristone and onapristone on the events of the menstrual cycle, since the progesterone antagonists prolong the menstrual cycle by delaying or blocking the LH surge. As a consequence, there is delayed or even absent ovulation, depending on the duration of treatment (Kettel et al., 1994
; Croxatto et al., 1998
; Brown et al., 2002
).
The ability to control endometrial bleeding by targeting the endometrium appears to be characteristic of 11-benzaldoxime substituted SPRMs with partial progesterone agonistantagonist activities since other compounds belonging to this class, including asoprisnil ecomate (J956; unpublished data) and J1042 (Chwalisz et al., 2000
) exhibit a similar effect in cynomolgus monkeys. Asoprisnil ecomate also induced amenorrhea in a dose-dependent manner in humans irrespective of the effects on luteinization (unpublished data). The exact mechanism of amenorrhea induced by 11
-benzaldoxime substituted SPRMs is still unknown. In cynomolgus monkeys, treatment with J1042 for 21 days significantly reduced the formation of spiral arterioles and were accompanied by endometrial atrophy, stromal compaction and the presence of weakly secretory glands (Chwalisz et al., 2000
). Endometrial atrophy was also observed in toxicological studies with asoprisnil in monkeys (Chwalisz et al., 2002
). Based on these studies we hypothesized that 11
-benzaldoxime substituted SPRMs may control both endometrial bleeding and proliferation via a vascular effect (Chwalisz et al., 2000
). This study revealed the formation of unusual, thick-walled arterioles in the endometrium of women exposed to asoprisnil (Figure 8B). In subjects treated with asoprisnil for 3 months or longer, thick-walled vessels are consistently found in Pipelle biopsies (unpublished data). These vessels clearly differ from those typically observed in the endometrium from women treated with continuous progestins. Such treatment results in the patchy appearance of abnormally small and abnormally large, thin-walled, fragile vessels in the superficial regions of exposed endometrium (Hickey et al., 2000
; Hickey and Fraser, 2000
; Simbar et al., 2004
). There is growing evidence to confirm that thin-walled microvessels are in some way linked to the troublesome symptoms of breakthrough bleeding and spotting in many women using long-acting progestins (Fraser and Hickey, 2000
). Hence, asoprisnil-induced morphological changes in endometrial vessels and perivascular stroma might be, at least in part, responsible for amenorrhea. The molecular mechanisms underlying these effects are still unclear.
In asoprisnil groups, there was no evidence of endometrial hyperplasia or other appearances indicative of unopposed estrogen effects on the endometrium in spite of follicular phase estrogen concentrations and non-luteal progesterone levels in many subjects. On the contrary, the endometrial biopsies conducted during the treatment period showed unique effects characterized by the presence of weakly secretory glands with minimal or absent proliferation, as evidenced by absent or rare mitotic figures, and variable effects in the stroma ranging from stromal compaction to focal predecidual reaction. These effects, described in the new classification system developed by TAP Pharmaceutical Products inc, Diagnostic Cytology Laboratories, and the expert panel of gynecological pathologists as non-physiologic secretory effects and secretory patterns, mixed type, have not been reported before with any other drugs. They are consistent with mixed progesterone agonist/antagonist effects on the glandular epithelium and stroma. Although secretory appearances of endometrial glands were weak, they were consistently observed at asoprisnil doses equal to and higher than 10 mg/day (Figure 8). In addition, no clear dose effect was evident. Longer studies with larger numbers of subjects are needed to fully assess the effects of asoprisnil on endometrial morphology. These studies are currently being conducted and will be published separately. The endometrial effects of asoprisnil seem to be different from those induced by progestins and progesterone antagonists such as mifepristone and onapristone. Although low doses of mifepristone (2 or 5 mg) decreased endometrial proliferation (Baird et al., 2003), proliferative patterns, rather than secretory effects, have been reported in premenopausal women treated with higher doses of mifepristone (Murphy and Castellano, 1994
). Indeed unopposed estrogenic effects with mifepristone may be seen with doses as low as 10 mg daily (Eisinger et al., 2003
; Steinauer et al., 2004
).
This study is consistent with animal studies indicating high PR selectivity of asoprisnil. With asoprisnil, there was no increase in C with any of the dose regimens, and the diurnal rhythm of C was maintained. Mean changes in DHEA-S concentrations were also inconsistent. This is all evidence that asoprisnil, unlike mifepristone, lacks antiglucocorticoid activity at the doses tested. This response was consistent with animal studies, which showed that asoprisnil has significantly less antiglucocorticoid activity than mifepristone (DeManno et al., 2003).
SHBG levels were suppressed by asoprisnil in a dose-dependent manner. SHBG is a liver protein that is increased by estrogens, decreased by androgens, but uninfluenced by progesterone (Rosner, 1990; Saarikoski et al., 1990
). The decrease in SHBG suggests an androgenic effect in the liver. A decrease in SHBG can potentially lead to an increase in fT, but uncertainties about the validity of the fT assay used in this study do not allow conclusions to be made about fT at this time. However, there were no significant changes in plasma lipids; neither were clinical androgenic effects (e.g. acne) apparent in these women. It must be stressed that this was only a 28-day study, and longer treatments are ongoing to determine if there is any interaction of asoprisnil with androgen receptors in humans.
Asoprisnil showed a favorable safety and tolerability profile in this study. The most commonly reported adverse events were headache, abdominal pain, nausea, dizziness and metrorrhagia. Minimal breakthrough bleeding occurred with asoprisnil with the exception of one woman who reported 15 days of intermittent spotting. Thus, unlike progestins, asoprisnil does not seem to induce breakthrough bleeding. Adverse events typical for progestins such as mood changes, bloating, etc., were not observed. There were also no concerns regarding ovarian cysts. Although longer studies will be needed to evaluate safety and tolerability of asoprisnil, the existing results are encouraging and support further clinical investigation.
In conclusion, the results of this study show that the SPRM asoprisnil in a total daily dose of up to 100 mg for 28 days was safe and well tolerated by premenopausal women. Asoprisnil reversibly prolonged the menstrual cycle and suppressed menstruation in a dose-dependent manner at doses >10 mg QD, irrespective of an effect on luteal phase progesterone concentrations indicative of luteinization. Asoprisnil induced these menstrual effects without compromising ovarian estrogen production, and induced amenorrhea primarily by targeting the endometrium and its blood vessels. These unique characteristics make asoprisnil a strong candidate for further development in the treatment of disorders such as uterine leiomyoma, endometriosis and abnormal uterine bleeding.
![]() |
Acknowledgements |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Brown A, Cheng L, Lin S and Baird DT (2002) Daily low-dose mifepristone has contraceptive potential by suppressing ovulation and menstruation: a double-blind randomized control trial of 2 and 5 mg per day for 120 days. J Clin Endocrinol Metab 87, 6370.
Chwalisz K, Brenner RM, Fuhrmann UU, Hess-Stumpp H and Elger W (2000) Antiproliferative effects of progesterone antagonists and progesterone receptor modulators on the endometrium. Steroids 65, 741751.[CrossRef][ISI][Medline]
Chwalisz K, Garg R, Brenner RM, Schubert G and Elger W (2002) Selective progesterone receptor modulators (SPRMs): a novel therapeutic concept in endometriosis. Ann N Y Acad Sci 955, 373388.
Chwalisz K, Lamar Parker R, Williamson S, Larsen L, McCrary K and Elger W (2003) Treatment of uterine leiomyomas with the novel selective progesterone receptor modulator (SPRM). J Soc Gynecol Invest 10, 636.
Chwalisz K, Larsen L, McCrary K and Edmonds A (2004) Effects of the novel selective progesterone receptor modulator (SPRM) Asoprisnil on bleeding patterns in subjects with leiomyomata. J Soc Gynecol Invest 11, 728.
Conn PM and Crowley WF Jr (1991) Gonadotropin-releasing hormone and its analogues. N Engl J Med 324, 93103.[ISI][Medline]
Croxatto HB, Kovacs L, Massai R et al. (1998) Effects of long-term low-dose mifepristone on reproductive function in women. Hum Reprod 13, 793798.[Abstract]
Croxatto HB, Salvatierra AM, Fuentealba B, Zurth C and Beier S (1994) Effect of the antiprogestin onapristone on follicular growth in women. Hum Reprod 9, 14421447.[Abstract]
DeManno D, Elger W, Garg R et al. (2003) Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy. Steroids 68, 10191032.[CrossRef][ISI][Medline]
Eisinger SH, Meldrum S, Fiscella K, le Roux HD and Guzick DS (2003) Low-dose mifepristone for uterine leiomyomata. Obstet Gynecol 101, 243250.
Elger W, Bartley J, Schneider B, Kaufmann G, Schubert G and Chwalisz K (2000) Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity. Steroids 65, 713723.[CrossRef][ISI][Medline]
Fraser IS and Hickey M (2000) Endometrial vascular changes and bleeding disturbances with long-acting progestins. Steroids 65, 665670.[CrossRef][ISI][Medline]
Hickey M, Dwarte D and Fraser IS (2000) Superficial endometrial vascular fragility in Norplant users and in women with ovulatory dysfunctional uterine bleeding. Hum Reprod 15, 15091514.
Hickey M and Fraser IS (2000) The structure of endometrial microvessels. Hum Reprod 15 (Suppl 3, 5766.
Hochberg Y (1988) A sharper Bonferroni procedure for multiple tests of significance. Biometrika 75, 800802.[ISI]
Kettel LM, Murphy AA, Morales AJ and Yen SS (1994) Clinical efficacy of the antiprogesterone RU486 in the treatment of endometriosis and uterine fibroids. Hum Reprod 9 (Suppl 1), 116120.[ISI][Medline]
Kurman RJ and Mazur MT (1994) Benign diseases of the endometrium. In Kurman RJ (ed.) Blaustein's Pathology of the Female Genital Tract. Springer-Verlag, New York, pp. 367409.
Kurman RJ and Norris HJ (1994) Endometrial hyperplasia and related cellular changes. In Kurman RJ (ed.) Blaustein's Pathology of the Female Genital Tract. Springer-Verlag, New York, pp. 411437.
Lobo RA and Stanczyk FZ (1994) New knowledge in the physiology of hormonal contraceptives. Am J Obstet Gynecol 170, 14991507.[ISI][Medline]
Murphy AA and Castellano PZ (1994) RU486: pharmacology and potential use in the treatment of endometriosis and leiomyomata uteri. Curr Opin Obstet Gynecol 6, 269278.[ISI][Medline]
Noyes R, Hertig AT and Rock J (1950) Dating the endometrial biopsy. Fertil Steril 1, 325.[ISI][Medline]
Rosner W (1990) The functions of corticosteroid-binding globulin and sex hormone-binding globulin: recent advances. Endocr Rev 11, 8091.[ISI][Medline]
Saarikoski S, Yliskoski M and Penttila I (1990) Sequential use of norethisterone and natural progesterone in pre-menopausal bleeding disorders. Maturitas 12, 8997.[ISI][Medline]
Simbar M, Manconi F, Markham R, Hickey M and Fraser IS (2004) A three-dimensional study of endometrial microvessels in women using the contraceptive subdermal levonorgestrel implant system, norplant. Micron 35, 589595.[CrossRef][ISI][Medline]
Steinauer J, Pritts EA, Jackson R and Jacoby AF (2004) Systematic review of mifepristone for the treatment of uterine leiomyomata. Obstet Gynecol 103, 13311336.[CrossRef][ISI][Medline]
Submitted on August 13, 2004; accepted on December 7, 2004.