Elagolix Represents a Less Invasive and Cheaper Option than Injectable GnRH Antagonist for Ovulation Suppression in IVF.

BACKGROUND: The injectable GnRH antagonists have traditionally been used for ovulation suppression during controlled ovarian hyperstimulation in IVF, leading to increased painful daily injections and cost. The use of the oral GnRH antagonist elagolix for ovulation suppression in IVF has not been studied. METHODS: A retrospective cohort study of patients undergoing IVF received either oral elagolix 50 mg every other day or ganirelix/cetrotide injection daily for ovulation suppression during controlled ovarian hyperstimulation. A total of 269 patients, 173 in the elagolix group and 96 in the ganirelix/cetrotide group, were included. The main outcome was the suppression of luteinizing hormone (LH) blood levels reflecting ovulation suppression. RESULTS: The age, body mass index, AMH levels, baseline FSH, antral follicles count, the dose of medications used, the number of days of ovarian stimulation, and peak estradiol (E2) levels were similar in both groups. When blood LH and E2 levels were measured before the intake and the day after intake of either elagolix or ganirelix/cetrotide, both groups had significant and similar drop in LH levels and increase in E2 levels. When comparing the IVF cycle outcomes in both groups, the number of oocytes retrieved, the number of mature oocytes, the fertilization rate, the blastocyst formation rate, the euploidy rate and the endometrial lining thickness at the time of the trigger were all similar. CONCLUSIONS: Oral GnRH antagonist, a much cheaper and less invasive medication that is used at a lower frequency, showed comparable ovulation suppression to the costly injectable GnRH antagonist. Further studies are required to evaluate the effect of oral GnRH antagonist on endometrial lining receptivity and pregnancy outcomes especially when using fresh embryo transfer IVF protocols.

The role of elagolix in the suppression of ovulation in donor oocyte cycles.

Objective: To study the clinical use of elagolix in ovarian stimulation and its effect on premature ovulation in a cohort of women undergoing oocyte donation. Design: A prospective cohort study with the use of historical controls. Setting: A private reproductive endocrinology and infertility clinic. Patients: Seventy-five oocyte donors and 75 historical donors, aged 21-30 years, who had each passed Food and Drug Administration and American Society for Reproductive Medicine-approved oocyte donor screening. Interventions: Administration of elagolix 200 mg orally every night at bedtime with development of a follicular size of ≥14 mm for ovulation suppression compared with ganirelix 250 µg every night at bedtime. Main Outcome Measures: Premature ovulation rate, total oocytes, mature oocytes, maximum estradiol, luteinizing hormone, and progesterone levels. Results: Oocytes were available in all retrievals because there were no instances of premature ovulation in either the elagolix or ganirelix groups. There were no statistically significant differences between the groups in baseline demographics. Both groups had the same amounts of gonadotropins consumed and days of stimulation. The average number of total oocytes was similar between the control group and elagolix group (30.55 vs. 30.31). Furthermore, the average number of mature oocytes was similar between the control and study groups (25.42 vs. 24.73). An analysis of the 580 fresh oocytes in the elagolix group and the 737 fresh oocytes in the ganirelix group showed similar outcomes with fertilization rates of 79.7% and 84.6%, respectively. Blastocyst development rates were also similar: 62.9% in the elagolix group and 57.3% in the ganirelix group. Conclusions: Compared with a historical control group using ganirelix, patients receiving elagolix demonstrated a similar number of oocytes and mature oocytes with on average 4.2 fewer injections per cycle and average per-cycle patient savings of $289.10. Clinical Trial Registration Number: Western IRB Pr. No.: 20191163, April 11, 2019. First enrollment June 20, 2019.

Evaluation of ovulation and safety outcomes in a multi-center randomized trial of three 84 day ulipristal acetate regimens.

OBJECTIVES: To describe ovulation inhibition and safety of daily oral ulipristal acetate (UPA) over 84 days. STUDY DESIGN: This multi-center phase 1 and/or 2 trial randomized participants to use oral ulipristal 10 mg or 5 mg daily or a 3 cycle regimen of 5 mg for 24 days followed by four placebo days. We stratified randomization by body mass index (BMI) <32 or 32-40 kg/m2. To estimate ovulation inhibition, the primary outcome, participants underwent transvaginal ultrasound and blood sampling twice weekly; we analyzed compliant participants who completed the 84 day study. Safety endpoints included 3 endometrial biopsies and liver chemistry tests. RESULTS: We enrolled 180 participants and included 137 in the ovulation inhibition analyses. Progesterone values that remained below 3ng/mL throughout treatment suggested consistent ovulation inhibition in 52 of 137 (38%) participants; 25 of 47(53%), 20 of 44(45%), and 7 of 46(15%) among participants randomized to the 10 mg, 5 mg, and cyclic treatments, respectively (p < 0.01). Progesterone values consistently <3 ng/mL were more frequent in participants with a BMI > 32kg/m2 (25/50(50%) vs 27/87(31%), p = 0.01). Average ulipristal concentrations were higher among participants with low progesterone concentrations (p < 0.01). Endometrial biopsies during treatment showed progesterone-receptor-modulator-associated endometrial changes in 52 of 164 participants (32%); 22 of 49(40%), 16 of 48(29%), and 14 of 51(26%) in women randomized to the 10 mg, 5 mg, and the cyclic treatments, respectively (p = 0.07, test-for-trend); these changes resolved after treatment cessation. Liver transaminase changes were rare. CONCLUSIONS: Oral ulipristal acetate over 12 weeks did not reliably suppress ovulation, particularly in the 5 mg cyclic-dose group. Ovulation inhibition and endometrial changes were dose dependent. Reversible endometrial changes occurred during treatment. IMPLICATIONS: Progesterone-receptor modulators have been suggested for daily oral contraception. Since progesterone concentrations suggest that ovulation occurred during treatment, further studies would be necessary to assess whether these were functional ovulations and to evaluate other possible mechanisms of contraception.

Phase I/II pharmacokinetic and pharmacodynamic evaluation of two levonorgestrel-only contraceptive patches in a multicenter randomized trial.

OBJECTIVES: To evaluate the pharmacokinetic and pharmacodynamic effects of two novel levonorgestrel (LNG)-only contraceptive patches. STUDY DESIGN: This multi-center Phase I/II trial randomized participants to use a 7-day transdermal patch designed to deliver a 40 mcg or 75 mcg daily LNG dose for 11 consecutive weeks; randomization was stratified by body mass index (BMI) <32 or 32-40 kg/m2. Evaluations occurred twice weekly for 5 weeks, then once weekly with supplemental visits for participants reporting a urinary LH surge. We evaluated pharmacokinetics via the weekly trough serum LNG concentrations (≥180 pg/mL considered therapeutic). The primary pharmacodynamic outcomes were cervical mucus and ovulation, evaluated using modified Insler cervical mucus scores and serum markers of ovulation. RESULTS: Randomization yielded similar groups. Of 121 enrolled women, 117 contributed analyzable data. Overall, mean LNG concentrations achieved with use of the 75 mcg patch [value] were roughly double those seen with the 40 mcg dose. Concentrations achieved in higher-BMI women (BMI=32-40 kg/m2) were 50% lower compared to lower-BMI women for both patches. During the study, 94/117 (80%) participants had at least one LNG concentration <180 pg/mL. Insler scores were ≥5 at least once in 102/117 (87%) of participants, and ovulation occurred at least once in 81/117 (69%). Sixty participants (51%) had at least one ovulation following an Insler score ≥5; this occurred most frequently among higher-BMI participants using the lower-dose patch (19/25, 76%). CONCLUSIONS: Women using two investigational LNG patches did not achieve consistent concentrations of LNG >180 pg/mL, an efficacy benchmark established in other studies with LNG implants, and they experienced high rates of ovulation as well as cervical mucus scores not supportive of high contraceptive efficacy. IMPLICATIONS: The novel LNG-only patches in this study may not adequately decrease pregnancy risk, particularly for higher-BMI women. Future studies of LNG-only contraceptive patches will need to employ higher LNG doses and assess the acceptability and safety of such dosing.

Why Stop Now? Extended and Continuous Regimens of Combined Hormonal Contraceptive Methods.

Combined hormonal contraceptives (CHCs) have traditionally been prescribed in 28-day cycles, with 21 days of active hormones followed by a 7-day hormone-free interval. Extended and continuous CHC regimens, defined as regimens with greater than 28 days of active hormones, offer many benefits, including a decrease in estrogen-withdrawal symptoms and likely greater efficacy because of more reliable ovulation suppression. Bleeding profiles are favorable, and unscheduled bleeding decreases over time with these regimens. Extended and continuous regimens of combined oral contraceptives and the contraceptive vaginal ring are safe and have high user acceptability and satisfaction. However, despite numerous benefits, extended and continuous CHC regimens are underused.

Effects of long-term low-dose mifepristone on reproductive function in women.

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.

A regimen of oral contraceptives restricted to the periovulatory period may permit folliculogenesis but inhibit ovulation.

Increased safety of oral contraceptives (OC) has resulted from a reduction in the estrogen and progestin content per tablet. A reduction in the number of hormonally active pills and their placement at critical points within the cycle may provide a novel regimen for further reducing the hormonal content of OC per cycle and their attendant side effects without compromising efficacy. The objective of this study was to determine the effectiveness of two OC regimens that incorporate a delayed start and limited midcycle use of the combination of ethinyl estradiol and norethindrone, and limited use of norethindrone only during the second half of the cycle. Main outcome measures were defined as ovulation, serum concentrations of estradiol (E2), luteinizing hormone (LH), follicle stimulating hormone (FSH), progesterone (P), follicular diameters, and endometrial thickness. Volunteers were issued blister packs containing 28 pills and randomized to one of two groups. Group 1 used a combination of 50 micrograms ethinyl estradiol and 1 mg norethindrone per tablet day 6-10, and 0.70 mg norethindrone only day 11-19. Placebo tablets were used on days 1-5 and day 20-28. Group 2 used a combination of 50 micrograms ethinyl estradiol and 1 mg norethindrone per tablet on day 8-12, and 0.70 mg norethindrone only on day 13-21. Placebo tablets were used on day 1-7 and day 22-28. A total of 20 cycles were studied using 10 volunteers. To assess any possible carryover effect, two successive cycles were studied for each subject. Serum sampling for E2, FSH, LH, and P, and transvaginal ultrasound imaging to assess endometrial thickness and follicle diameter were carried out at 4 day intervals throughout the cycle. One ovulation occurred in 10 cycles in group 1. Five ovulations occurred in 10 cycles in group 2. All ovulations, regardless of group, occurred in the second cycle. Peak E2 concentrations were not significantly different between groups (152.04 +/- 107.1 pg/mL vs 162.1 +/- 56.1 pg/mL [mean +/- SD] for groups 1 and 2, respectively] but occurred earlier in the cycle in group 1. No differences were noted between the groups in serum concentrations of FSH or LH for any given cycle day. Maximum follicle diameters were not different between groups 1 and 2, regardless of ovulatory status (20.5 +/- 8.1 mm2 vs 20.6 +/- 14.2 mm2, respectively). Ultrasound imaging assessment of midcycle follicle growth revealed diameters ranging from 18.5 mm2 to 34.0 mm2 with gradual resolution through the second half of the cycle in anovulatory cycles, and 16.0 mm2 to 23.5 mm2 with abrupt disappearance in ovulatory cycles. Endometrial thickness did not exceed 10 mm for any anovulatory cycle regardless of group, but ranged from 6 to 9 and 6 to 11 during the luteal phase of ovulatory cycles of groups 1 and 2, respectively. Peak serum P concentrations at midluteal phase in ovulatory cycles ranged from 9.2 ng/ml to 18.2 ng/ml. Data from this preliminary study suggest that ovulation may be prevented with a combination of ethinyl estradiol and norethindrone started as late as cycle day 6 and limited to 5 days' duration using norethindrone only for 9 days during the second half of the cycle. Such a restricted regimen may offer both an effective method of contraception and a means of further reducing both estrogen and progestin content per cycle and the possible short and long term adverse side effects of these hormones.

PIP: A reduction in the number of hormonally active oral contraceptive (OC) pills and their placement at critical points within the cycle represents a novel potential regimen for further reducing the hormonal load of OCs per cycle and the attendant side effects without compromising efficacy. The present study evaluated the effectiveness of two such OC regimens: group 1--placebo tablet on days 1-5, 50 mcg of ethinyl estradiol and 1 mg of norethindrone per tablet on days 6-10, 0.70 mg of norethindrone only on days 11-19, and placebo tablets on days 20-28; and group 2--placebo tablet on days 1-7, 50 mcg of ethinyl estradiol and 1 mg of norethindrone per tablet on days 8-12, 0.70 mg of norethindrone only on days 13-21, and placebo on days 22-28. 10 volunteers were randomized to one of the two groups for two cycles. There was 1 ovulation in the 10 cycles completed in group 1 and 5 ovulations in the 10 cycles in group 2. All ovulations occurred in the second cycle. Peak estradiol concentrations occurred earlier in the cycle in group 1, but were not significantly different between groups. Serum concentrations of follicle-stimulating hormone or luteinizing hormone and mean follicle diameters were not different between groups. Folliculogenesis occurred in all 20 cycles. Mid-cycle follicular growth resolved gradually during the second half of the cycle in anovulatory cycles and abruptly in ovulatory cycles. The length of the luteal phase for ovulatory cycles was 7 days in group 1 and 8-12 days in group 2. These findings suggest ovulation may be prevented with a combination of ethinyl estradiol and norethindrone started as late as cycle day 6 and limited to 5 days' duration, using norethindrone only for 9 days during the second half of the cycle.

Contraceptive potential of a mifepristone-nomegestrol acetate sequential regimen in women.

The effectiveness of a sequential regimen consisting of mifepristone, 10 mg/day for 15 days, followed by nomegestrol acetate (NOMA), 5 mg/day for the next 13 days, for inhibiting ovulation and maintaining regular bleeding cycles was assessed in 10 surgically sterilized volunteers who were followed for one pretreatment and three treated cycles. Hormonal determinations in blood and urine, ovarian ultrasonography, bleeding records in all cycles and an endometrial biopsy taken on day 22-25 of the third treatment cycle were used to monitor the effects of treatment. During treatment, 24 monophasic (no sustained progesterone rise above 12 nmol/l) and six biphasic cycles were recorded. Nine follicular ruptures were detected echographically in these 30 treated cycles, five of which occurred in monophasic cycles. All follicular ruptures occurred on days 1-7 of NOMA treatment. Echographic and endocrine features of ovulatory cycles were both present in only four treated cycles (13.3%). Development of a secretory endometrium was achieved in all cases, but it was always irregular. Regular withdrawal bleeding occurred in all subjects and no adverse reactions were recorded. The ovarian and endometrial effects of this regimen justify testing its contraceptive effectiveness in phase 2 clinical trials.

PIP: This study investigated the efficacy of mifepristone, 10 mg/day for 15 days, followed by nomegestrol acetate (NOMA), 5 mg/day for the next 13 days, for inhibiting ovulation and maintaining regular bleeding cycles in 10 surgically sterilized volunteers. To monitor the effects of treatment, hormonal determinations in blood and urine, ovarian ultrasonography, bleeding records in all cycles and endometrial biopsy were taken on day 22-25 of the third treatment cycle. About 24 monophasic and 6 biphasic cycles were recorded during treatment. About 9 follicular ruptures were echographically detected in these 30 cycles, 5 of which occurred in monophasic cycle. All follicular ruptures occurred in days 1-7 of NOMA treatment. Echographic and endocrine features of ovulatory cycles were both present in only four treated cycles (13.3%). Development of a secretory endometrium was achieved in all cases, but it was always irregular. Regular withdrawal bleeding occurred in all subjects and no adverse reactions were observed. The ovarian and endometrial effects of this regimen justify testing its contraceptive effectiveness in phase 2 clinical trials.

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.

Oral contraceptive pills. Prevention of ovarian cancer and other benefits.

PIP: Each year, about 25,000 new cases of ovarian cancer are diagnosed in the US. Because ovarian cancer has few symptoms in its early stages and there is no effective screening test, most patients have widespread metastases at diagnosis. Epidemiologic studies have demonstrated that OC use can protect against ovarian cancer for at least 15 years after pill use is discontinued. The most likely mechanism of this protective effect is inhibition of ovulation. A strong association between total number of lifetime ovulations and mutation of the p53 gene in ovarian cancers has been reported. Use of the pill for 5 years decreases the risk of ovarian cancer by 40% but decreases lifetime ovulations by only about 15%, suggesting that factors other than prevention of proliferation-associated mutations contribute to the protective effect of ovulation inhibition. The pill also decreases the incidence of endometrial cancer by about 50%. At present, OCs represent the best option for US women from both the contraceptive and cancer prevention perspectives.^ieng

Effect of once weekly administration of mifepristone on ovarian function in normal women.

The effects of mifepristone on ovarian function during a once weekly oral administration regimen were studied in nine healthy women. Each received 25 mg mifepristone on cycle days 3, 10, 17, and 24. Ovulation, as documented by hormonal measurements and ultrasonography, was inhibited during treatment in five subjects, with a midcycle surge of luteinizing hormone and ovulation occurring 6-18 days after the last pill was administered in four of the five subjects. These five treatment cycles were prolonged 9-26 days. The other four subjects had normal cycles as judged by serum hormone levels, ultrasonography, and cycle length. All nine subjects had delayed endometrial growth as indicated by ultrasonography. There was a significant correlation between concentrations of serum mifepristone (10 h and 58 h) and alpha 1-acid glycoprotein, the protein to which mifepristone binds in circulation. Response to mifepristone did not depend on its circulating levels. We conclude that once weekly administration of 25 mg mifepristone can interfere with normal follicular development and function, but the inhibition of ovulation was inconsistent.

Modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest.

Twenty-two healthy female volunteers with normal ovulatory cycles, aged between 20 and 34 years (27.3 +/- 4.1), were included in a single-center, noncomparative study to investigate the modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest. At baseline, during three treatment cycles and post-treatment, serum levels of luteinizing hormone, follicle-stimulating hormone, 17 beta-estradiol, and progesterone were assayed and ultrasonography was used to measure follicular size and the thickness of the endometrium. The primary efficacy variable was inhibition of ovulation as measured by ovarian activity grading. All volunteers ovulated during the pretreatment cycle. During treatment, none of the subjects had ovulatory cycles, although there was still some ovarian activity in several subjects. During the first treatment cycle, only 4% (1 subject) of cycles showed active follicle-like structures. The frequency of follicle-like structures increased to 33% and 35% during treatment cycles 2 and 3. The frequency of presumptive luteinized unruptured follicle-like structures was 5% (1 subject) and 15% (3 subjects) in treatment cycles 2 and 3. The serum hormone concentrations were effectively suppressed in comparison to baseline. The ovarian activity returned to baseline during the post-treatment period. One subject was excluded from further study because of a medical problem believed unrelated to use of the oral contraceptive. No serious adverse events were recorded during the course of the study. The results of the present investigation indicate that the modulatory effects on ovarian function of the monophasic oral-contraceptive containing 30 micrograms ethinyl estradiol combined with 2.00 mg dienogest lead to adequate suppression of ovarian activity and effective inhibition of ovulation.

Effect of follicular phase administration of mifepristone (RU486) on blastocyst implantation in the rhesus monkey.

In the present study our aim was to test two hypotheses: 1) inhibition of preovulatory phase progesterone action can inhibit or delay ovulation, and 2) inhibition of preovulatory phase progesterone action can inhibit postovulatory phase endometrial receptivity for blastocyst implantation. Female rhesus monkeys showing normal cycle lengths were randomly assigned to two groups: group 1 (n = 5) and group 2 (n = 7). The pretreatment cycles were monitored for ovulatory pattern and, in treatment cycles, females were allowed to cohabit with males from cycle days 6 to 28; group 1 animals received vehicle alone, and group 2 animals received mifepristone (RU486, subcutaneously), 1 mg/animal 3 consecutive cycle days (days 7, 8, and 9 for 26-day pretreatment cycle length; and days 8, 9, and 10 for 28-day pretreatment cycle length). Follicular phase mifepristone resulted in a delay of ovulation (p < 0.01) when compared with pooled data of pretreatment and treatment cycles of group 1 and pretreatment cycles of group 2. Despite delay of ovulation, there was only a 20% decrease in the incidence of pregnancy in group 2 as compared with that in group 1. However, a delay (p < 0.05) in the appearance of CG was noted in follicular phase mifepristone-treated cycles as compared with control treatment cycles. On the other hand, ovulation could not be detected in three monkeys in group 2; and, of these, two cycles were extended, but all three cycles were negative for CG. These results support earlier reports that follicular phase mifepristone can inhibit or disrupt follicular maturation, and delay ovulation. However, follicular phase mifepristone failed to inhibit implantation, because gonadal hormones, including progesterone, resume normal functions once ovulation takes place.

PIP: Available research evidence suggests that, when administered during the follicular phase, a high affinity antiprogestin such as mifepristone can act at different levels of the hypothalamus-pituitary-ovary-uterus axis, resulting in contraceptive action. The administration of mifepristone during the late follicular phase of naturally mated cycles of rhesus monkeys was used to test the hypotheses that inhibition of preovulatory phase progesterone action can: 1) inhibit or delay ovulation, and 2) inhibit postovulatory phase endometrial receptivity for blastocyst implantation. During the preovulatory period, group 1 monkeys (n = 5) were treated with 1 mL vehicle and group 2 animals (n = 7) received mifepristone for 3 consecutive days. Peripheral hormone profiles suggested no ovulation occurred in 3 of 8 mifepristone-treated cycles. Follicular phase mifepristone treatment was associated with a delay of ovulation in 4 of 8 treated cycles. Despite the delay of ovulation, there was only a 20% decrease in the incidence of pregnancy in group 2 compared to group 1. A delay in the appearance of chorionic gonadotropin was noted in follicular phase mifepristone-treated cycles. These findings confirm that mifepristone treatment during the late follicular phase can inhibit or delay ovulation without affecting uterine function during the luteal phase. Further studies are required using this primate model to investigate the role of progesterone and other physiological modulators on ovulation and implantation.

A comparative randomized trial on the impact of two low-dose oral contraceptives on ovarian activity, cervical permeability, and endometrial receptivity.

In a double-blind randomized study, the suppression of ovarian activity and anti-conceptive effects on the cervix and endometrium were assessed during administration of two low-dose monophasic oral contraceptives (20 micrograms ethinyl estradiol [EE], 500 micrograms norethisterone--Eve 20 [Grünenthal, Aachen, Germany]; 20 micrograms EE, 150 micrograms desogestrel --Lovelle [Organon, Munich, Germany]). One hundred eighteen healthy women (ages: 18-35 years) were studied in 10 investigation centers during medication with either Eve 20 (n = 59) or Lovelle (n = 59). During three treatment cycles, ovarian activity was evaluated by sonographic determination of follicle-like structures (FLS) and by simultaneous assessment of serum endocrine profiles (gonadotropins LH and FSH, ovarian steroids estradiol [E2] and progesterone [P]). While on either treatment, no ovarian activity (as judged by no FLS and/or reduced sex steroid levels) was found in 90.8% (Eve 20) and 97.2% (Lovelle) of all investigated cycles. Follicular activity or cyst formation were detected in 18 of 173 cycles (Eve 20) and in 5 of 175 cycles (Lovelle), respectively. Gonadotropin levels were suppressed (LH < 6 IU/L, FSH < 8 IU/L) in most treatment cycles (Eve 20 76.6% vs. Lovelle: 84.8%). Serum E2 concentrations exceeding 0.1 nmol/L indicated residual follicular activity in 19.3% (Eve 20) versus 12.2% (Lovelle) of all cycles. An estimated by serum P levels over 5 nmol/L, ovulation had presumably occurred in 4.1% (Eve 20) versus 2.9% (Lovelle) of treatment cycles. However, when the sonographical and endocrinological data were combined, no ovulation was documented in any pill cycle. The quality and quantity of the cervical mucus was found to be minimal in the majority of women. Moreover, the endometrial layer was determined to be low by ultrasound during most pill cycles, indicating equally strong suppressive effects on endometrial receptivity by the two contraceptives. These observations suggest that ovarian activity is suppressed in the majority of cycles during use of low-dose contraceptives. This effect may mainly be medicated by pronounced suppression of serum gonadotropin levels. Strong anti-conceptive effects of these formulations on both cervical permeability and endometrial receptivity are additional factors ensuring the contraceptive efficacy of these formulations.

PIP: The impact of two low-dose monophasic oral contraceptives (OCs) on suppression of ovarian activity, cervical permeability, and endometrial receptivity was investigated in a randomized double-blind study involving 118 healthy women 18-35 years of age recruited from 10 study centers in Germany. 59 women received Eve (20 mcg of ethinyl estradiol and 500 mcg of norethisterone) and 59 were given Lovelle (20 mcg of ethinyl estradiol and 150 mcg of desogestrel) for a total of 3 cycles. No ovarian activity, as assessed by sonographic determinations of follicle-like structures and serum endocrine profiles, was detected in 90.8% of cycles of Eve users and 97.2% of cycles in the Lovelle group. Follicular activity or cyst formation was found in 18 of 173 cycles of Eve users and 5 of 175 cycles of Lovelle users. Gonadotropin levels were suppressed (luteinizing hormone under 6 IU/L and follicle-stimulating hormone less than 8 IU/L) in 76.6% of treatment cycles in the Eve group and 84.8% of cycles in the Lovelle group. Serum estradiol concentrations exceeding 0.1 nmol/L, indicative of follicular activity, were recorded in 19.3% of cycles of Eve users and 12.2% of cycles in the Lovelle group. Although serum progesterone levels were over 5 nmol/L in 4.1% of cycles in the Eve group and 2.9% of those in the Lovelle group, consolidation of sonographic and endocrinologic data failed to document ovulation in any treatment cycles. The quantity and quality of cervical mucus was minimal in most women in both groups. Finally, the endometrial layer was determined to be low by ultrasonography during most pill cycles, confirming the OCs' equally strong suppressive effects on endometrial receptivity.

The possible use of antiprogestins for contraception.

BACKGROUND: A number of compounds, antiprogestins, e.g. mifepristone, onapristone and lilopristone, have been developed which compete with progesterone at the receptor level. One of these, mifepristone, is in combination with a prostaglandin analogue currently in use for termination of early pregnancy. The possibility to use these compounds for contraceptive purposes is presently under evaluation. METHODS: The possible contraceptive effect of antiprogestins has been evaluated in both clinical and experimental studies. RESULTS: Administration of antiprogestin during the follicular phase has an inhibitory effect on follicular development and ovulation, and on endometrial development and function if administered during the secretory phase of the menstrual cycle. A high dose of mifepristone, 200 mg, administered immediately following ovulation is highly effective in preventing implantation, most likely due to an effect on endometrial receptivity. It seems that the endometrium is more sensitive to antiprogestin than is the ovulatory process. Low weekly, 2.5 mg to 5 mg, and daily doses, 0.5 mg, of mifepristone did not inhibit ovulation, but a significant effect on endometrial development and especially endometrial function judged from measurement of the expression of a number of markers for endometrial receptivity could be demonstrated. CONCLUSION: The effect of mifepristone on the endometrium may be sufficient to prevent implantation, and if so, an oral contraceptive method could be developed which has no effect on ovarian function.

PIP: The potential use of antiprogestins such as mifepristone and onapristone for contraceptive purposes is currently under investigation. Administration of antiprogestins during the follicular phase of the menstrual cycle delays the estrogen rise and the luteinizing hormone surge. As long as treatment is continued, follicular development is delayed or arrested and ovulation is inhibited. It is assumed that the inhibitory effect of antiprogestins on ovulation is mediated by a blocking effect of progesterone on the pituitary level. A 200-mg dose of mifepristone, administered immediately after ovulation, is highly effective in preventing implantation. Although a daily dose of 0.5 mg of mifepristone does not inhibit ovulation, it has a significant effect on endometrial development and receptivity. Intermittent administration of mifepristone, together with periodic administration of a gestagen, both inhibits ovulation and induces regular withdrawal bleeding. The current research indicates that the endometrium is more sensitive to mifepristone than is the ovulatory process. If such effects are sufficient to prevent implantation, a contraceptive method based on very low doses of antiprogestin and without any effect on bleeding patterns is feasible.

Ovarian activity during regular oral contraceptive use.

The aim of this study was to assess whether during regular OC use ovarian activity might lead to ovulation, as assessed by ultrasound (US) evaluation of follicular growth and blood levels of 17-beta-estradiol and progesterone. A total of 51 healthy women with normal menstrual cycles (28 +/- 3 days) and no gynecological symptoms were recruited. A total of 22 patients were given a triphasic OC pill containing 35 mg ethinyl estradiol (EE) and 50 mg desogestrel (DSG) in the first seven tablets; 30 mg EE and 100 mg DSG in tablets 8 to 14, and 30 mg EE and 150 mg DSG in tablets 15 to 21; 29 patients received one of two OC pills, both containing 20 mg EE plus 150 mg DSG (15 patients) or 75 mg of gestodene (14 patients). A total of 86 cycles were monitored: 51 during the 3rd-4th cycle and 35 during the 6th-8th cycle of OC treatment. Follicular-like structures were observed in nine patients. The frequency of follicular-like structures was similar during the 3rd-4th cycle (9%) and during the 6th-8th cycle (11%). There was no relationship between follicular growth and blood levels of E2 and progesterone, which always appeared suppressed. In conclusion, the results of this study suggest that during OC use (even with low dose of ethinyl estradiol), a little ovarian activity may be present without ovulation.

PIP: Several studies have described a 10-20% incidence of folliculogenesis during low-dose oral contraceptive (OC) use. This study used ultrasound evaluation of follicular growth and blood levels of 17-beta-estradiol and progesterone to determine whether OC-induced ovarian activity led to ovulation in 51 healthy women with regular menstrual cycles. Subjects were given a new triphasic OC containing 35 mg ethinyl estradiol (EE) and 50 mg desogestrel (DSG) in the first 7 tablets, 30 mg EE and 100 mg DSG in tablets 8-14, and 30 mg EE and 150 mg DSG in tablets 15-21 (22 women); an OC containing 20 mg EE and 150 mg DSG (15 women); or an OC comprised of 20 mg EE and 75 mg gestodene (14 women). A total of 86 cycles were monitored: 51 during the third and fourth cycles and 35 during the sixth through eighth cycles of treatment. Follicular-like structures were observed in 9 patients. Follicular growth occurred in 4 cycles (11%) in the triphasic group, 3 (13%) in the EE-DSG group, and 2 (7%) in the EE-gestodene group. The frequency of follicular-like structures was similar during the third-fourth cycle (9%) and the sixth-eighth cycle (11%). There was no association between follicular growth and blood levels of estradiol and progesterone. These results are compromised by the fact that only 35 of the 51 subjects completed 2 cycles. Nonetheless, they tend to confirm the observation that even a low dose of ethinyl estradiol can produce some ovarian activity without ovulation.

Inhibition of ovulation by an oral contraceptive containing 100 micrograms levonorgestrel in combination with 20 micrograms ethinylestradiol.

Twenty-four healthy female volunteers with normal ovulatory cycles, aged between 20 and 34 years (27.5 +/- 4.3), were included in a single-center, non-comparative study to investigate the effect on inhibition of ovulation of an oral contraceptive containing 20 micrograms ethinylestradiol in combination with 100 micrograms levonorgestrel. At baseline, during three treatment cycles and post-treatment, ultrasonography was used to examine the ovaries, to measure follicular size, and to measure the thickness of the endometrium. Serum levels of LH, FSH, estradiol, progesterone, total testosterone, free testosterone, SHBG, and CBG were also measured. Compared with treatment cycle 1, an increase in residual ovarian activity (follicle grades 4-5) was observed in cycles 2 and 3. Mean levels of LH, FSH, 17 beta-estradiol and progesterone remained suppressed during treatment. No escape ovulation was observed during the treatment phase of the study and there were no pregnancies. Ovulation was noted to return rapidly in the posttreatment cycle. Subjective and objective tolerance of the present regimen was noted to be good. Results indicate that the monophasic oral contraceptive containing 100 micrograms levonorgestrel combined with 20 micrograms ethinylestradiol effectively inhibits ovulation, providing adequate suppression of ovarian activity.

Pharmacokinetics of mifepristone after low oral doses.

Relatively low doses of the antiprogestin mifepristone (RU 486) have recently proven to be efficient for a variety of possible clinical uses of the drug. However, the pharmacokinetics after low single oral doses have not been characterized. We evaluated the pharmacokinetics of mifepristone following single ingestion of 2 and 25 mg in five women as well as repeated ingestion of 8 mg in two women. Maximal serum concentrations were reached rapidly (within 0.5-2 h) with all doses used. Serum mifepristone concentrations were proportional to the oral doses taken. The mean (+/- SD) areas under the concentration curves (AUCs) (0-24 h) were 1134 (+/- 144), 4846 (+/- 64), and 17,015 (+/- 4,421) h x ng/mL following 2, 8, and 25 mg doses, respectively. No cumulative increases in serum concentrations were detected with prolonged daily administration of 8 mg of mifepristone. The study subjects appeared to vary in their ability to metabolize mifepristone, as two different half-lives (t1/2) emerged after both 2 and 25 mg single doses (24.2 +/- 0.6 [SD] h for three subjects; and 44.4 +/- 1.8 [SD] h for two subjects). We conclude that within the dose range of 2-25 mg/day, the pharmacokinetics of mifepristone are linear, unlike those seen following ingestion of higher daily doses. Keeping in mind previously published data on the biological effects of low dose mifepristone administration, these data infer that certain effects of the drug, such as inhibition of ovulation, might be achieved at serum concentrations of approximately 100 ng/mL.

PIP: At the outpatient clinic of Lohja District Hospital in Lohja, Finland, clinical researchers examined the pharmacokinetics of mifepristone in 5 healthy women, 29-37 years old, receiving a single dose of 2 mg mifepristone and of 25 mg mifepristone and in 2 other women receiving 8 mg mifepristone each day for 30 days. Regardless of the dose, serum concentrations of mifepristone peaked within 1.2-1.4 hours. These concentrations were proportional to the oral doses: 104-227 ng/ml after 2 mg dose; 474-561 ng/ml after 8 mg dose; and 1285-4851 ng/ml after 25 mg dose. The areas under the concentration curves (0-24 hours) were also proportional to the oral doses: 1134.4, 4846, and 17,015.2, respectively. Daily doses of 8 mg mifepristone over 30 days did not effect cumulative increases in serum concentrations. The women taking the 2 mg and 25 mg single oral doses exhibited different half-lives (24.2 [3 women] vs. 44.4 [2 women] hours; p = 0.001), suggesting that they varied in their ability to metabolize mifepristone. These findings show that, at daily ingestion of 2-25 mg mifepristone, the pharmacokinetics of mifepristone are linear. Based on these findings, the authors think that inhibition of ovulation might be achieved at serum concentrations of about 100 ng/ml.

Effects of a sequential regimen of mifepristone-medroxyprogesterone acetate on ovarian function, endometrial development and hormonal parameters.

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.

Mifepristone: a potential contraceptive.

Use of standard estrogen-progestin contraception remains problematic in several subgroups of patients (e.g., those in whom exogenous estrogens are contraindicated, such as survivors of hormone-dependent cancer, or patients with endometriosis or uterine fibroids). In addition, the postcoital contraception, even if already available, remains at least underused. Additionally, continuous intake of contraceptive steroids is under increasing scrutiny. Would antiprogestins, and specifically the applications of mifepristone such as the ones reviewed in this article offer significant improvements at such problematic occasions? The most attractive novel contraceptive application of mifepristone is that of emergency postcoital contraception after unprotected intercourse. In addition, various options in the endometrial category, specifically those requiring drug administration only during a limited time, might be used in the future. Mifepristone might offer contraceptive and therapeutic relief to patients suffering from endometriosis or uterine fibroids, both conditions that have been shown to benefit from mifepristone therapy. However, the use of mifepristone in contraceptive preparations that are widely available would pose an additional problem of possible misuse of the compound, the reason for currently limiting access to mifepristone. However, such risk should be easily avoidable in the case of postcoital contraception in which only one dose of mifepristone is needed. Regarding the future of mifepristone, and more broadly that of antiprogestins in contraception, the authors believe that they will have a place in the future contraceptive armament. As already emphasized, the strongest clinical areas are those of immediate postcoital and endometrial contraception. Additional studies evaluating parenteral modes of administration, the long-term endometrial effects, and safety and metabolic effects of prolonged antiprogestin administration are needed before mifepristone can be considered a part of the contraceptive arena.

PIP: The evaluation of mifepristone (RU-486) as a potential contraceptive has entailed three strategies: endocrine, endometrial, and postcoital. Both animal and human studies have indicated that continuous preovulatory administration of RU-486 (at least 2 mg/day) inhibits ovulation, presumably through its perturbation of the hypothalamo-pituitary-ovarian axis and disruption of normal folliculogenesis. However, the return of menses after RU-486 termination is unpredictable. Early luteal phase or continuous RU-486 administration eliminates this side effect and delays endometrial maturation. On the other hand, late luteal phase administration of a high single dose is associated with failure rates of 3-16%. The use of RU-486 for immediate postcoital contraception lengthens the subsequent menstrual cycle, but is highly effective and well tolerated. At present, the immediate postcoital and endometrial strategies appear most promising. Urged is further research evaluating parenteral modes of administration, the long-term endometrial effects, and the safety and metabolic effects of prolonged antiprogestin use.