Contraceptive efficacy of daily administration of 0.5 mg mifepristone.

The antiprogestin mifepristone has shown potential to be used as a contraceptive. If 200 mg mifepristone is administered immediately after ovulation, the endometrium shows sufficient impairment of secretory development to prevent implantation. Low daily doses of mifepristone have been shown to reduce several of the local factors regarded as crucial for implantation in human endometrium. To find out if this regimen is sufficient to prevent pregnancy, 32 women were recruited for a study where 0.5 mg mifepristone was administered daily. A total of 141 cycles were studied. Five pregnancies occurred, which was significantly less than if no contraceptive method had been used. However, the dose chosen did not seem sufficient to act as a contraceptive although it is probably not possible to increase the dose without disturbing ovulation and bleeding pattern.     

Uterus and endometrium: Effects of daily low dose mifepristone on endometrial maturation and proliferation

Following an ovulatory control cycle, six women took 2 mg ofmifepristone daily for 30 days. Endometrial biopsies were collectedin the control cycle between 7 and 11 days after the plasmaluteinizing hormone (LH) surge and on the corresponding dayof the treatment cycle (days 19–28). In order to investigatethe effects of unopposed oestrogen on the endometrium, persistentproliferative endometrium was obtained from six women with anovulatoryinfertility due to polycystic ovarian syndrome (PCOS) on a similarcycle day (days 21–23) following a progestogen-inducedwithdrawal bleed. Endometrium was evaluated for histology andimmuno-localization of oestrogen receptors (ER), progesteronereceptors (PR) and the cell proliferation markers [proliferatingcell nuclear antigen (PCNA) and Ki67]. Treatment with mifepristoneinhibited ovulation in four of the six subjects. In the twosubjects in whom ovulation did occur, secretory transformationwas delayed, suggesting that successful implantation of a blastocystwould be unlikely. In subjects who remained anovulatory duringtreatment, the histology and pattern of steroid receptor expressionwas similar to proliferative phase endometrium. In women withPCOS, mitoses and intense immunostaining for ER, PR and cellproliferation markers were observed in both glands and stroma.Although PCNA and Ki67 immunostaining were also present in mifepristone-treatedendometrium from subjects who did not ovulate, there were nomitoses and significantly less ER immunostaining in spite ofexposure to unopposed oestrogen for a similar duration. SincePCNA and Ki67 detect cells throughout all stages of the cellcycle this would suggest that mifepristone might affect theentry of cells into the mitotic phase of the cell cycle and,therefore, might prevent endometrial hyperplasia. These findingsadd further evidence to support the contraceptive potentialand antiproUferative activity of daily low dose mifepristone.     

Prediction of ovulation by urinary hormone measurements with the home use ClearPlan Fertility Monitor: comparison with transvaginal ultrasound scans and serum hormone measurements

The timing of sexual intercourse in relation to ovulation strongly influences the chance of conception. Daily serum LH measurements or transvaginal ultrasonography are not practical to determine ovulation in consecutive cycles for an individual. A prospective study was initiated to test the home use performance of the ClearPlan Fertility Monitor (CPFM) in ovulation prediction compared with transvaginal ultrasonography and serum hormone measurements. A total of 53 women aged 18-39 years with a normal uterus and at least one ovary, cycle length between 21-42 days and not using medication which interferes with ovarian function contributed 150 cycles for analysis. One cycle was anovulatory and no LH surge, indicating peak fertility, was detected by the monitor. Of the remaining 149 cycles, 135 (90.6%) had a monitor LH surge and ultrasonographically confirmed ovulation. Ovulation was detected in 91.1% of cycles during the 2 days of CPFM peak fertility. Ovulation was observed in 51.1% of cycles 1 day and in 43.2% of cycles 2 days after the surge in serum LH. Ovulation never occurred before CPFM peak fertility or the serum LH surge day. CPFM can help women who desire pregnancy to time intercourse. It may also have potential as a diagnostic aid and for monitoring the treatment of infertility.     

Effect of low daily doses of mifepristone on ovarian function and endometrial development

The effects of low daily doses of the antiprogestin mifepristone (RU 486) on ovarian and endometrial function were studied. The study included one control cycle, three treatment cycles and one follow-up cycle. During the treatment cycles, either 0.1 (n = 5) or 0.5 (n = 5) mg of mifepristone was administered once daily. Urine samples were collected three times weekly during the control and treatment cycles and pregnanediol glucuronide and oestrone glucuronide and luteinizing hormone (LH) were quantified by radioimmunoassay. Blood samples for cortisol measurement were collected once weekly and for serum glycodelin at the onset of menstruation. An endometrial biopsy was obtained in the mid-luteal phase in the control cycle and in the first and third treatment cycles and analysed by morphometric and histochemical methods. Binding of Dolichus biflorus agglutinin (DBA) lectin was measured and expression of progesterone and oestrogen receptors and glycodelin were analysed immunohistochemically. All cycles studied were ovulatory with an LH peak and elevated pregnanediol glucuronide concentrations. Follicular development seemed normal as judged by ultrasound examination. The length of the menstrual cycle and the menstrual bleeding were not significantly altered. Following administration of 0.5 mg mifepristone/day, endometrial development appeared to be slightly retarded and glandular diameter was significantly reduced. Furthermore, significant decreases in DBA lectin binding and endometrial expression of glycodelin were observed. Daily doses of 0.1 mg did not have any significant effect on the endometrium. No differences in oestrogen or progesterone receptor immunoactivity between control and treatment cycles were seen. This study provides further evidence that endometrial function is sensitive even to doses of antiprogestin that are low enough not to disturb ovulation. It remains to be established whether these effects are sufficient to prevent implantation.      

Andrology: Failure of oestrogen induced luteinizing hormone surge in women treated with mifepristone (RU 486) every day for 30 days

It has been demonstrated previously that administration of theantiprogestin mifepristone (RU 486; 1–5 mg daily) inhibitsor delays both the pre-ovulatory luteinizing hormone (LH) surgeand ovulation. To investigate this mechanism, dynamic testsof pituitary ovarian function were performed in six healthywomen before and during the administration of mifepristone (2mg daily for 30 days). On day 9 of the control and treatmentcycles, samples of blood were collected every 15 min over 12h for measurement of LH concentration. After 10 h, the responsivenessof the pituitary was tested by the i.v. injection of 10 µgof gonadotrophin-releasing hormone (GnRH). On day 10 of thecontrol and treatment cycles, two patches releasing 200 µg/dayof oestradiol were applied to skin on the abdomen for 3 days.Blood was collected at 24, 48, 59, 72, 81 and 96 h after applicationof the oestrogen patches for the measurement of gonadotrophinand ovarian hormone concentrations. Follicular development continuedin all women during their treatment with mifepristone, and ovulationwas suppressed (four women) or delayed (two women). There wasno significant difference in the basal concentration of LH betweenthe control and treatment cycles (mean ± SE; 5.5 ±0.4 versus 7.7 ± 0.4 IU/l respectively), or in the frequency(interpulse interval, 101 ± 12 versus 105 ± 13min respectively) and the amplitude (2.1 ± 0.4 versus2.6 ± 0.4 IU/l respectively) of LH pulses. The responseto GnRH was similar. On day 10, the basal concentrations ofLH, follicle-stimulating hormone (FSH), prolactin, oestradioland progesterone and the diameter of the dominant follicle (15.7± 1.8 versus 13.3 ± 1.9 mm) were similar duringcontrol and treatment cycles. In control cycles, there weresignificant increases in the concentrations of LH and FSH within72 h of application of the oestrogen patches. During treatmentcycles, concentrations of FSH and LH remained low, and weresignificantly lower than the values observed during controlcycles (P < 0.006). We conclude that the antiprogestin mifepristonedisrupts ovulation by inhibiting the positive feedback effectof oestrogens and, hence, prevents or delays the generationof a pre-ovulatory LH surge.     

Feasibility of administering mifepristone as a once a month contraceptive pill

Many women find the idea of a once-a-month contraceptive pill an attractive concept. Mifepristone has been shown to be effective as a contraceptive if administered in the early luteal phase. We tested the contraceptive efficacy of 200 mg of mifepristone on day luteinizing hormone (LH) + 2 in a group of 32 women who used a fertility monitor to identify the LH surge. We also recruited a control group, comprising 20 women who were trying to conceive. In this group, 12 women conceived during a total of 50 control cycles (probability of pregnancy 0.25-0.32). Women in the treatment group contributed to a total of 178 cycles and there were two pregnancies (probability of pregnancy 0.01). An LH surge was not detected in 34 cycles (19.1%). In 20 cycles (11.2%) this was due to imperfect use while 14 were monitor method failures (7.9%). Treatment with mifepristone in the early luteal phase did not disrupt the cycle length but women reported slight vaginal bleeding in 15% of the cycles. The combination of a home-use fertility monitor with once-a-month administration of mifepristone (especially if mifepristone is administered at the early luteal phase) is an acceptable contraceptive option with minimal side effects. Unfortunately, it is difficult to envisage how an easier way of defining the correct timing, which required less compliance, could be devised.     

Physiology: Effects of intermittent antiprogestin RU486 combined with cyclic medroxyprogesterone acetate on folliculogenesis and ovulation

The results of several studies have suggested an inhibitoryeffect of the antiprogestin RU486 on late stages of folliculogenesisand ovulation. To assess the feasibility of using this propertyto inhibit ovulation without losing cycle control, an intermittentadministration of RU486 alternated with medroxyprogesteroneacetate (MPA) was tested in a phase I study. RU486 at a doseof 50 mg/day was given on menstrual cycle days 9–11 and27–29, and 10 mg/day of MPA was given on cycle days 17–26for three consecutive cycles to six Finnish and five Chileanwomen. Blood samples were collected two to three times a weekfor serum progesterone and oestradiol assays in three treatmentcycles. One control cycle and one post-treatment recovery cyclewere also monitored by serum samplings. Ultrasonography wascarried out to measure follicular diameters in the treatmentcycles. In 29 of 32 cycles, bleeding commenced within 3 daysafter the last MPA pill intake. Out of 32 treatment cycles,20 were without luteal activity (serum progesterone <9 nmol/l).Although 12 treatment cycles showed luteal activity (serum progesterone9 nmol/l), a clear rupture of a pre-ovulatory follicle >15mm, verified by ultrasonography, was seen in only one treatmentcycle. During the treatment cycles with luteal activity (serumprogesterone levels 9 nmol/1), serum oestradiol concentrationswere significantly higher on cycle days 9–18 and significantlylower at the end of the cycle compared with the cycles withoutluteal activity. The regimen used in this study disturbed folliculogenesisand ovulation (apparently), and was able to provide good cyclecontrol in the majority of the cycles.     

Effect of long-term treatment with low-dose mifepristone on the endometrium

BACKGROUND: Mifepristone in low daily doses has contraceptive potential by inhibiting ovulation and menstruation. Because follicular development is maintained, the endometrium is exposed to estrogen for prolonged periods unopposed by progesterone. METHODS: Endometrial biopsies were collected from 90 women in Edinburgh and Shanghai before (late proliferative) and 60 and 120 days after taking 2 or 5 mg mifepristone per day for 120 days. RESULTS: Ovulation and menstruation were inhibited in >90% of cycles and estrogen production was similar to that observed during the follicular phase of the control cycle. By 120 days, endometrial thickness increased significantly in women in Edinburgh but decreased in Shanghai. Endometrial histology showed inactive proliferative or cystic changes with dense stroma. There was a significant decrease in markers of proliferation, i.e. mitotic index and Ki67 staining. There were no pregnancies in a total of 200 women-months in 50 sexually active women who used no other method of contraception. CONCLUSIONS: We confirm that ovulation and menstruation were suppressed in the majority of cycles and there was asynchrony between ovarian activity and endometrial histology, which showed no signs of hyperplasia or atypia. These preliminary data suggest that daily low-dose mifepristone is potentially a safe estrogen-free contraceptive pill which has the added health benefit of amenorrhoea.     

Endocrinology: Effect of mifepristone (RU486) on the pituitary response to gonadotrophin releasing hormone in women

Mifepristone interrupts folliculogenesis in women but the mechanismis not clear. Previous studies have investigated the effectof this compound on gonadotrophin secretion and have providedconflicting results. To study further the effect of mifepristoneon basal and gonadotrophin-releasing hormone (GnRH)-inducedgonadotrophin secretion, 12 normally ovulating women were investigatedduring two consecutive menstrual cycles, comprising an untreatedcycle (control) and a cycle treated with mifepristone. All womenwere treated with mifepristone on days 2–8 at the doseof 100 mg (group 1, eight women) or 10 mg per day (group 2,six women). Two women were treated with both regimens in twodifferent cycles. On day 8 of both cycles, the women receivedtwo GnRH pulses of 10 µg each 2 h apart. Blood samplesin relation to the first GnRH pulse were taken at –15,0, 30, 60, 120, 150, 180 and 240 min. In group 1, the increasein luteinizing hormone (LH) in response to GnRH was significantlyattenuated from 30 to 180 min, while the increase in folliclestimulating hormone (FSH) was attenuated only in response tothe second GnRH pulse. No significant decrease in LH and FSHresponse to GnRH was seen during treatment with the 10 mg dose(group 2). In group 1, serum oestradiol and inhibin-A concentrationsafter day 8 were lower than in the control cycles and the LHpeak was postponed by 7 days on average. Basal LH values increasedsignificantly on day 8 in both groups, while FSH values didnot change significantly compared with the control cycles. Asignificant increase in serum progesterone and cortisol valuesoccurred during the treatment only in group 1. Mid-luteal valuesof inhibin-A were significantly lower in cycles treated with100 mg mifepristone than in the control cycles. We concludethat the disruption of folliculogenesis by mifepristone cannotbe explained by a decrease in basal FSH concentrations duringthe critical period of follicle recruitment and selection. Itis possible that mifepristone exerts its effect at the levelof the ovary. It is also suggested that progesterone duringthe follicular phase of the cycle may participate in the controlof the self-priming action of GnRH on the pituitary.     

A novel estrogen-free oral contraceptive pill for women: multicentre, double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel)

BACKGROUND: The acceptability and continuation rate of oral contraceptive steroids are limited by unpredictable bleeding and the fear of long-term risks such as breast cancer. By inhibiting ovulation and by altering the receptivity of the endometrium, antagonists of progesterone, such as mifepristone, could be developed as estrogen-free novel contraceptives. METHODS: Multicentre, double-blind, randomized controlled trial comparing frequency of amenorrhoea (primary outcome), bleeding patterns, side effects and efficacy in women taking daily 5 mg mifepristone (n = 73) or 0.03 mg levonorgestrel (progestogen-only pill; POP, n = 23) for 24 weeks. RESULTS: More women were amenorrhoeic while taking mifepristone than POP (49 versus 0% P < 0.001), and fewer women bled or spotted for >5 days per month (4 versus 39% P < 0.001). Forty-eight percent of women who took mifepristone for 6 months had cystic glandular dilatation of the endometrium but none showed hyperplasia or atypia. There were no pregnancies in 356 months of exposure in women who used only mifepristone for contraception. Two pregnancies occurred in women taking mifepristone who were also using condoms for dual protection. CONCLUSIONS: Daily mifepristone (5 mg) is an effective oral contraceptive pill which has a better pattern of menstrual bleeding than an existing POP (levonorgestrel).     

Inhibition of ovulation by low-dose mifepristone (RU 486).

Mifepristone (RU 486) is a potent antigestagen and antiglucocorticoid which when given at a dose of 25-600 mg disrupts folliculogenesis, inhibits ovulation and induces menses in healthy women. This study reports the effects of much lower doses of mifepristone than used previously, given for the duration of a complete menstrual cycle. Healthy female volunteers (n = 11) with regular menstrual cycles were given mifepristone at a daily dose of 5 mg (n = 6) or 2 mg (n = 5) for 30 days, beginning immediately after an ovulatory placebo cycle. Mifepristone prevented menstruation for the duration of the treatment period, with recurrence of menses 15-29 days after replacement of mifepristone with placebo. Daily mifepristone given in either 5 mg or 2 mg doses inhibited ovulation, as indicated by the lack of a rise in urinary pregnanediol excretion. The excretion of oestrone glucuronide in urine rose during treatment, suggesting ovarian follicular development. Inhibition of ovulation appeared to result from a failure of the positive feedback effect of oestradiol on the hypothalamo-pituitary axis, as no surges of luteinizing hormone were seen despite pre-ovulatory levels of oestrone glucuronide being measured during exposure to mifepristone. The cycle immediately following treatment was shorter than the pre-treatment cycle, with lower peak levels of pregnanediol glucuronide, suggesting an inadequate luteal phase. Recovery from the effects of mifepristone treatment was more rapid after 2 mg than after 5 mg and one subject conceived in the immediate post-treatment phase, indicating adequate ovulation and luteinization.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ovulation prediction and detection with the CUE? Ovulation Predictor

Predicting ovulation is useful for managing the infertile patientand when done sufficiently in advance for fertility regulationby periodic abstinence. It has been reported that ovulationcould be predicted by measurement of salivary and vaginal electricalresistance (SR and VR). These data from 32 menstrual cyclesof 23 women were obtained to evaluate this technique. Data of14 cycles were from subjects receiving clomiphene citrate (CC),while the others were from spontaneously ovulating subjects.A peak in SR was seen 5–7 days before the day of the LHpeak in both natural and CC cycles. A correlation coefficient(r) of 0.94 was seen for the day of the SR peak and that ofthe LH peak. The SR trend was similar in both natural and CCcycles. VR in spontaneous cycles declined to a periovulatorynadir and then increased. The patterns of VR in CC cycles weresimilar except that values were initially depressed during andshortly after the end of CC therapy. Over 90% of VR increaseswere on the day of the LH peak and the day following. Resultsindicate that the method is useful for predicting ovulationin natural and CC cycles. Since the number of days by whichovulation is predicted exceeds the expected lifespan of spermatozoain the female reproductive tract, the method also shows potentialfor use in natural family planning.     

Ovary and Ovulation: Home ovulation testing In a donor insemination service

The use of home ovulation testing kits in donor insemination(DI) has been proposed to increase patient and clinic conveniencewhile not compromising fecundity rates. Such a system was introducedinto our Dl service in December 1994, and we here report anaudit of experience over 6 months. Patients were offered homeor laboratory luteinizing hormone (LH) testmg, and those requestinghome testing were asked to store an aliquot of tested urinefor subsequent assay in the laboratory allowing retrospectiveanalysis of the accuracy of cycle timing. Insemination usingcryopreserved semen was performed on the day home testing predictedovulation, or on the day an LH surge was detected in the laboratory,and on the following day. Pregnancy rates were significantlyreduced in home testers: 3.4% per cycle (174 cycles, 64 women)versus 12.7% (110 cycles, 53 women) over the same time period(P<0.005, 95% confidence interval 6.5–18.9). Urinesamples from 140 cycles from 51 women using home testing wereanalysed. There were insufficient data in nine to allocate thecycle. Of home tested cycles, 37 (28%) were inseminated on aday other than the first day of the LH surge. In 13 of theseinsemination was performed after the first day of the LH surge.Incorrect treatment was associated with high baseline LH, butthose with ‘late’ treatment had low basal LH concentrations,similar to those correctly treated. Analysis of individual urinesamples showed that the positive predictive value of home testingwas 72%. These results suggest that home ovulation testing resultsin reduced chance of pregnancy, with increased frustration forboth patients and clinic staff. This may be particularly soin women with high baseline LH concentrations.     

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.      

Effect of low weekly doses of mifepristone on ovarian function and endometrial development

The effect of a low dose of mifepristone (RU486) on ovarianand endometrial function was studied in 14 healthy women. Thestudy included one control and two treatment cycles. Duringthe treatment cycles, either 2.5 mg (n = 9) or 5 mg (n = 5)of mifepristone was administered once weekly. The concentrationof ovarian steroids and luteinizing hormone (LH) in urine wasmeasured daily, cortisol in blood once weekly and glycodelin(placental protein 14; PP14) at the time of menstruation. Ovarianfunction was monitored by vaginal ultrasound. An endometrialbiopsy was taken in each cycle in the mid-luteal phase, basedon self-measurement of the LH peak, or on cycle day 22 if noLH peak could be detected. In the evaluation of the results,the outcome of the enzyme immunoassay of LH was used to datethe biopsy. Endometrial progesterone and oestrogen receptorsand Dolichus biflorus agglutmin (DBA) lectin binding were measured.Ovulation was not inhibited by treatment with mifepristone,and an LH peak could be determined in all control and treatmentcycles. However, in four subjects (one with the higher and threewith the lower dose) the follicular phase was prolonged by 6–13days. The duration of the luteal phase and the concentrationsof pregnanediol and oestrone glucuronide were not affected bytreatment A dose of 5 mg, and to a lesser extent 2.5 mg, mifepristoneonce weekly caused desynchron-ization of endometrial developmentEndometrial progesterone receptor, but not oestrogen receptor,concentration was significantly increased by the higher dose.A significant reduction in DBA-lectin binding and in serum glycodelinconcentrations was also found. Thus, low doses of mifepristonedo not inhibit ovulation but delay endometrial development andimpair secretory activity. Whether these effects are sufficientto prevent implantation remains to be established.     

Validation of the dual analyte assay of the oestrone: pregnanediol ratio in monitoring ovarian function

The purpose of this study was to validate the dual analyte system(Boots Celltech Ltd, Slough, UK) as a marker of ovarian function.For this purpose the urinary profile of the ratio of oestrone-3-glucuronideto pregnanediol-3-glucuronide in urine (E13G/PD3G) was comparedwith plasma concentrations of oestradiol, progesterone, luteinizinghormone (LH) and follicle stimulating hormone from day 8–24of the menstrual cycle in 23 women. Daily transvaginal ultrasoundwas also performed from day 8 of the cycle until sonographicevidence of follicular rupture. The ratio of urinary metabolitesexhibited a maximum value close to ovulation. In the majorityof cases this coincided with the day of LH peak, and was followedby follicular rupture within the next 24 h in 74% of cases.The assay gives a good marker of ovulation, however, it is unlikelyto help in detecting the initiation of the fertile period orthe quality of the menstrual cycle.     

The effectiveness and safety of recombinant human LH to support follicular development induced by recombinant human FSH in WHO group I anovulation: evidence from a multicentre study in Spain.

BACKGROUND: Until recently, human menopausal gonadotrophin (HMG), a urinary extract containing a fixed combination of LH and FSH, was the only source of exogenous LH for women with hypogonadotrophic hypogonadism undergoing ovulation induction with gonadotrophins. Recombinant human LH (rLH) is now available for clinical use, providing a new treatment option but clinical data on its use are scanty. Therefore, the aim of the present study was to investigate the efficacy and safety of rLH combined with recombinant FSH (rFSH) to induce follicular development and ovulation in World Health Organization (WHO) group I anovulatory women. METHODS: We included in this multicentre study 38 hypogonadotrophic anovulatory (WHO group I) women. Patients received 150 IU/day rFSH and 75 IU/day rLH (with the possibility of dose adjustment) as a single s.c. injection for up to three cycles with a total of 84 treatment cycles. RESULTS: Sufficient follicular growth was observed in 79 (94%) out of 84 initiated cycles. The 75 IU rLH dose was found to be effective in most treatment cycles (94%) and only five cycles in three patients required daily dose increase. Overall, HCG was administered to trigger ovulation in 67 (80%) of the 84 cycles while it was withheld in 12 cycles (14%) due to ovarian hyper-response and five cycles (6%) were cancelled for insufficient follicular growth. The pregnancy rate per started treatment cycle and per cycle given HCG was 18 and 22.4% respectively. Pregnancy was achieved by 15 (39.5%) of the 38 patients. Mild to moderate ovarian hyperstimulation syndrome occurred in three patients. Local tolerance was good. CONCLUSIONS: This study confirms that combined rFSH and rLH treatment induces follicular growth, ovulation and pregnancy in a good proportion of hypogonadotrophic anovulatory patients and is well tolerated. The doses of 150 IU rFSH and 75 IU rLH daily seem the most appropriate but in a small minority of patients doses >75 IU rLH/day may be necessary.     

Luteal phase ovarian oestrogen is not essential for implantation and maintenance of pregnancy from surrogate embryo transfer in the rhesus monkey

The aim of this study was to investigate whether luteal phaseovarian oestrogen is required for blastocyst implantation andpregnancy maintenance in the rhesus monkey. Preimplantationembryos were retrieved from naturally ovulated, mated embryodonor monkeys. In group I, developmentally normal, age- andstage-matched embryos were transferred to recipient monkeysshowing naturally synchronized ovulatory cycles. Immediatelyprior to embryo transfer, recipients were subjected to bilateralovariectomy, and following transfer they were treated with i.m.injections of either progesterone (group Ia, n= 4), or oestradiol+ progesterone (group Ib, n= 2). Recipient monkeys of groupIc (n= 4) were subjected to sham ovariectomy and vehicle injection.In group Ia, progesterone supplementation alone led to threepregnancies and live births. In group Ib, there was one livebirth. In the control group Ic, four transfers resulted in twolive births and one abortion on cycle day 58. Analysis of serumprogesterone and oestradiol profiles showed that oestradiolhad declined to undetectable levels within 3–5 days afterovariectomy in group Ia recipients, and the area under the curveof serum oestrogen concentrations during the peri-implantationperiod (days 10–20 after ovulation) were less (p< 0.001)in group Ia compared with group Ic. There were no changes inthe area under the curve among serum progesterone concentrationsin all the subgroups. In group II, long-term ovariectomizedembryo recipients (n= 4) were primed with oestradiol till cycleday 11 of simulated transfer cycle, and received progesteronetreatment from cycle day 10 till the end of the experiment.Of four transfers, live births were recorded in two cases, whilein one case abortion occurred on cycle day 66. Serum oestradiolconcentrations were undetectable during the presumptive peri-implantationperiod of pregnancy cycles in group II recipient monkeys. Noyes‘dating of endometrial samples collected from both groups ondays 5–7 after the oestrogen rise revealed that endometrialhistology synchronized well with those found during days 3–5after ovulation in normal menstrual cycle. We conclude thatluteal phase ovarian oestrogen is not essential for progesterone-dependentendometrial receptivity and response leading to implantationand pregnancy maintenance in the rhesus monkey.     

Anti-nidatory effect of a single, early post-ovulatory administration of mifepristone (RU 486) in the rhesus monkey

The hypothesis that post-coital administration of mifepristone(RU 486) as a single dose in the early luteal phase can be aneffective anti-nidatory strategy was tested using the rhesusmonkey as the experimental model. Incidence of pregnancy, vaginalbleeding patterns, profiles of menstrual cyclicity and of serumlevels of progesterone and oestrogen were examined followingadministration of RU 486 as a single dose of 10 mg/kg and 2mg/kg body weight on the second day after ovulation. In controlmonkeys (group 1; n = 5) receiving the vehicle alone (benzylbenzoate: olive oil, 1: 4, v/v) there was a 60% pregnancy rate.Following s.c. administration of RU 486 at both doses, no pregnancywas recorded in a total of 33 treatment cycles in 12 monkeys.Five monkeys received RU 486 at 10 mg/kg s.c. (group 2) in threeconsecutive cycles. All animals had complete inhibition of implantation;in addition, the treatment cycle length was prolonged (P <0.001) due to an extension of the luteal phase. The subsequentfollicular phase was unaffected. Mild, premature vaginal bleedingduring the luteal phase was recorded in five treatment cycles,3–5 days after drug application. Though the serum profilesof progesterone and oestrogen in these monkeys showed markedindividual variations, there was a characteristic progesteronerebound about 18–20 days after drug administration. Monkeysin group 3 were given RU 486 at 2 mg/kg, s.c. either for threeconsecutive cycles (group 3a; n = 4) or for two consecutivecycles (group 3b; n = 3). Premature luteal phase vaginal bleedingoccurred only in four treatment cycles, within 2–6 dayspost-treatment. An increase in both the duration (P < 0.001)and degree (P < 0.001) of menstrual flow as compared withthe pre-treatment cycles was recorded in six treatment cyclesof three monkeys in group 3. These animals did not have prematureluteal phase vaginal bleeding. Collectively, 100% protectionagainst pregnancy with no change in the cycle length was obtainedin all seven monkeys in 18 treatment cycles. Analysis of pooleddata revealed that the subsequent follicular phase, as wellas the ovarian steroid hormone profiles of treatment cycleswere unaffected. Thus, a single application of RU 486 in theearly secretory phase appears to be a potential anti-implantationstrategy for intercepting pregnancy in the primate.     

Follicular growth during contraceptive pill or vaginal ring treatment depends on the day of ovulation in the pretreatment cycle

BACKGROUND: The aim of this study was to investigate whether the day of ovulation and the duration of a pretreatment cycle were related to the degree of follicular growth during subsequent contraceptive treatment. METHODS: This randomized, open-label study was performed in 40 healthy female volunteers, who were randomized by a computer-generated list after stratification for the ovulation day in a pretreatment cycle. They received two cycles of NuvaRing (21 subjects) or a combined oral contraceptive (COC) containing 30 microg ethinylestradiol and 150 microg levonorgestrel (19 subjects). Follicular diameter and serum hormone concentrations (FSH, LH, 17beta-estradiol, progesterone) were measured every third day. Data from treatment day 20 onwards were used for analysis. RESULTS: In the NuvaRing users, subjects with short cycles and early ovulations in the pretreatment cycle developed larger follicles during treatment than subjects with longer cycles and late ovulations. In the COC users, subjects with early ovulations in the pretreatment cycle developed larger follicles during treatment. CONCLUSIONS: The degree of follicular growth during treatment with a combined hormonal contraceptive is influenced by the duration of the pretreatment cycle and particularly by the duration of the follicular phase.