HIRA contributes to zygote formation in mice and is implicated in human 1PN zygote phenotype.

Elucidating the mechanisms underpinning fertilisation is essential to optimising IVF procedures. One of the critical steps involves paternal chromatin reprogramming, in which compacted sperm chromatin packed by protamines is removed by oocyte factors and new histones, including histone H3.3, are incorporated. HIRA is the main H3.3 chaperone governing this protamine-to-histone exchange. Failure of this step results in abnormally fertilised zygotes containing only one pronucleus (1PN), in contrast to normal two-pronuclei (2PN) zygotes. 1PN zygotes are frequently observed in IVF treatments, but the genotype-phenotype correlation remains elusive. We investigated the maternal functions of two other molecules of the HIRA complex, Cabin1 and Ubn1, in mouse. Loss-of-function Cabin1 and Ubn1 mouse models were developed: their zygotes displayed an abnormal 1PN zygote phenotype. We then studied human 1PN zygotes and found that the HIRA complex was absent in 1PN zygotes that lacked the male pronucleus. This shows that the role of the HIRA complex in male pronucleus formation potentially has coherence from mice to humans. Furthermore, rescue experiments in mouse showed that the abnormal 1PN phenotype derived from Hira mutants could be resolved by overexpression of HIRA. We have demonstrated that HIRA complex regulates male pronucleus formation in mice and is implicated in humans, that both CABIN1 and UBN1 components of the HIRA complex are equally essential for male pronucleus formation, and that rescue is feasible.

Clinical pregnancy is significantly associated with the blastocyst width and area: a time-lapse study.

In order to maintain pregnancy rates following single embryo transfer, optimisation of embryo culture and selection is vital. Time-lapse monitoring (TLM) has the potential to play a crucial role by providing sequential images of embryo development and minimal disturbance. Therefore, in this study morphometric assessment of blastocyst area and maximum width was performed in order to evaluate if these parameters are associated with pregnancy outcomes in IVF/ICSI cycles. This is a retrospective study of 664 patients who had elective single blastocyst transfer (eSBT). The EmbryoScope drawing tools were used to measure specific variables such as the maximum blastocyst width and blastocyst area. Our results show that women who were pregnant had significantly (P < 0.01) larger blastocyst width [median (range) µm] 184 (125-239) versus non-pregnant, 160 (120-230)] and area [median (range) µm2] 26099 (12101-45,280) versus non-pregnant women, 22,251 (10992-37,931)]. A univariate logistic regression performed showed that blastocyst width [(OR = 1.026, 95% CI = (1.019, 1.033)] was significant (P < 0.01) and for every µm increase of blastocyst width, the odds of clinical pregnancy increase by 2.6%. A univariate logistic regression performed showed that blastocyst area [(OR = 1.00008, 95% CI = (1.00006, 1.00011)] was significant with P < 0.01. For every µm2 increase of blastocyst area, our data showed the odds of clinical pregnancy increase by 0.008%. Hosmer-Lemeshow tests of calibrations were performed to verify calibration. Although our findings show a clear correlation between blastocyst dimensions and the clinical pregnancy rate, further studies are necessary to confirm these observations.

Spontaneous blastocyst collapse as an embryo marker of low pregnancy outcome: A Time-Lapse study.

OBJECTIVE: In this study we investigate the correlation between spontaneous blastocyst collapse and pregnancy outcome. METHODS: This is a retrospective study performed at Edinburgh Assisted Conception Programme, EFREC, Royal Infirmary of Edinburgh, UK. Embryos were cultured individually in 6.0% CO2, 5.0% O2, 89.0% N2, using single step medium (GTL™ Vitrolife, Göteborg, Sweden) and selected for transfer using standard morphological criteria. Using the EmbryoScope™ time-lapse monitoring (TLM), blastocysts collapse was analyzed by measuring the maximum volume reduction and defined as having collapsed if there was >50% volume reduction. Couples undergoing IVF/ICSI treatment and having an elective single embryo transfer (eSET) at blastocyst stage were included in this study. After the embryo transfer, retrospectively, each blastocyst was allocated to one of two groups (collapsed or not collapsed). 62 blastocysts collapsed once or more during development (17.4%), the remaining 294 showed no collapse (82.6%). RESULTS: A significantly higher implantation rate (IR) of 61.2% and ongoing pregnancy rate (OPR) of 53.7% was observed when blastocysts which had not collapsed were replaced compared to cycles in which collapsed blastocysts were replaced (IR rate 22.6% and OPR 17.7%). CONCLUSION: This study demonstrated that human blastocysts which collapse spontaneously during in vitro development are less likely to implant and generate a pregnancy compared with embryos which do not. Although this is a retrospective study, the results establish the utility of collapse episodes as new marker of embryo selection following eSET at blastocyst stage.

Increased pregnancy outcome after day 5 versus day 6 transfers of human vitrified-warmed blastocysts.

Vitrification is a highly efficient technique for the cryopreservation of the human embryo. The effect of delayed blastulation may be responsible for implantation failures and negatively affects in vitro fertilization (IVF) outcomes. The current literature displays discordant results; some studies have announced higher pregnancy rates after day 5 (D5) transfer compared with day 6 (D6) transfer, while others have shown equivalent outcomes. In the present study an investigation into the clinical implications of delayed blastulation (D5 versus D6) was carried out. We performed a retrospective study comparing clinical pregnancies and implantation rates following warmed single blastocyst transfer (WSBT). All patients coming for a programmed warmed transfer at Edinburgh Assisted Conception Programme, EFREC, Royal Infirmary of Edinburgh, were included in this study and divided in two groups according to the day of blastocyst vitrification: D5 (n = 1563) and D6 (n = 517). The overall survival rate was 95.0% (1976/2080) with no significant difference between the D5 and D6 groups: 95.3% (1489/1563) and 94.2% (487/517) respectively. WSBT of D6 blastocysts resulted in a lower implantation and clinical pregnancy compared with D5 embryos. The implantation rate (IPR) and clinical pregnancy rate (CPR) were respectively 49.4% and 42.6% for the D5 and 37.4% and 32.2% for the D6 embryos, which was statistically significant. The multiple pregnancy rate was 1.32% (1.14% for D5 vs 1.84% for D6). Although the transfer of D6 vitrified-warmed blastocyst remains a reasonable option, priority to a D5 embryo would reduce the time to successful pregnancy.

Single blastocyst transfer (SET) and pregnancy outcome of day 5 and day 6 human blastocysts vitrified using a closed device.

This study investigates the utility of the Rapid-i closed device for vitrification of human blastocysts on day-5 (D5) and day-6 (D6) of development and the implantation and pregnancy rate following single blastocyst transfer (SBT) of warmed D5/D6 blastocysts. This retrospective cohort study was performed at Edinburgh Assisted Conception Programme, EFREC, Royal Infirmary of Edinburgh between January 2013 and January 2017. Good quality blastocysts were vitrified on D5 or D6 using Irvine Vitrification medium (Irvine Scientific-USA) and the Rapid-I closed Vitrification System™ (Vitrolife, Sweden). After warming, blastocysts were cultured in G-TL™ medium (Vitrolife) supplemented with 20% HSA-solution™ (Human Serum Albumin) for 2 h before the transfer. The survival, pregnancy and implantation rates were compared in relation to the day of culture at the time of vitrification (D5/D6) in 1090 cryopreserved cycles. The overall survival rate was 93.4% (1018/1090) with no significant difference between the D5 and D6 groups: 93.9% (712/758) and 92.2% (306/332) respectively. Single embryo transfers of D6 vitrified/warmed blastocysts resulted in a lower implantation and clinical pregnancy rate compared to D5 embryos. The implantation rate (IPR) and clinical pregnancy rate (CPR) were respectively 49.6% and 43.0% for the D5 and 37.0% and 33.0% for the D6 embryos, which was statistically significant. The multiple pregnancy rate was 1.08% (0.98% for D5 vs 1.3% for day 6).

Fifteen year follow-up of embryos cryopreserved in cancer patients for fertility preservation.

PURPOSE: Determine the outcome of embryo cryopreservation in female oncology patients METHODS: The outcomes of IVF/ICSI cycles in oncology patients over 15 years in a University Teaching Hospital. RESULTS: Forty-two oncology patients (mean 31.9 ± 3.9 years) underwent embryo cryopreservation treatment (n = 33 IVF, n = 6 ICSI). Controlled ovarian stimulation with GnRH antagonist protocol (n = 34; 81 %) yielded fewer oocytes than GnRH agonist protocol (n = 8; 19 %) (9.4 ± 6.3 vs. 15.3 ± 8.9; p = 0.04) respectively. There was no significant difference in mean (±SD) duration of ovarian stimulation (11.6 ± 2.6 vs.10.6 ± 2.7), median gonadotrophin dose (1950 vs. 1670 IU), median day 5-6 oestradiol level (1124 vs.1129 pmol/l) or embryo yield (6.2 ± 4.1 vs. 8.8 ± 4.3; p = 0.07) between GnRH antagonist and agonist treatment cycles respectively. Thirty-nine patients cryopreserved embryos and three had their cycle cancelled. During this study period, of those who cryopreserved embryos, 5 patients underwent 9 frozen-thaw cycles (13 %), resulting in 2 live births (1 twin, 1 singleton, live birth rate 22 %). Six patients died (15 %), 3 conceived naturally (8 %) and 2 couples separated (5 %). Fourteen patients discarded their embryos (36 %). Twenty-two patients' (56 %) have embryos remaining in storage. CONCLUSIONS: This study demonstrates that embryo cryopreservation in female oncology patients gives a satisfactory live birth rate. However, there are concerns regarding cost-effectiveness, resulting from high disposal/non-usage of embryos, and further studies are required.

Lack of impact of semen quality on fertilization in assisted conception.

BACKGROUND: Defective semen quality is one of the commonest causes of infertility. The diagnosis of male fertility depends upon a descriptive evaluation of human semen, however a normal semen analysis does not necessarily indicate satisfactory fertility potential. AIMS: (i) to examine the semen quality of patients undergoing treatment by assisted conception, (ii) to explore relationships between semen quality and treatment outcomes, and (iii) to look at inter-laboratory variation in the assessment of semen quality. METHODS: Semen quality in patients undergoing assisted conception treatment between 2001 and 2004 was reviewed. Data on female age, egg numbers and fertilization outcomes was obtained by case note review. RESULTS: The thresholds used to direct patients towards IVF or ICSI treatment were comparable with the normal values promulgated by WHO, with the exception of morphology. Semen quality was not predictive of fertilization rates. When the results of independent measurements of the same sample were compared, there was diagnostic disagreement in between 10%-29% of samples. CONCLUSIONS: The conventional criteria of semen quality are used to determine treatment strategy for couples undergoing assisted conception but are not reflected in fertilization rates, emphasising the limited utility of the conventional criteria of semen quality in the assessment of sperm function. There remains significant inter-laboratory variation in the results of semen analysis.

Cumulus gene expression as a predictor of human oocyte fertilisation, embryo development and competence to establish a pregnancy.

The close relationship between cumulus cell function and oocyte developmental competence indicates that analysis of cumulus gene expression is a potential non-invasive method to aid embryo selection and IVF outcome. Cumulus was isolated from 674 oocytes from 75 women undergoing ICSI and gene expression analysed by quantitative RT-PCR. Cumulus expression of cyclooxygenase 2 (PTGS2) was higher with mature oocytes, whereas brain-derived neurotrophic factor (BDNF) was lower when fertilisation was normal. Expression levels of gremlin (GREM1) and BDNF were weak positive and negative predictors of embryo quality respectively. Ranking of GREM1 expression within cohorts of oocytes showed that oocytes associated with the highest GREM1 expression were more likely to be transferred or cryopreserved than discarded (49 vs 33%, P<0.02), although the clinical pregnancy rate was not significantly different. This study demonstrates both the feasibility and difficulties of this method of analysis in the largest such group studied thus far. Novel relationships between BDNF expression and fertilisation were identified, and the potential value of GREM1 expression as a marker of embryo quality supports the further assessment of GREM1 analysis in the context of embryo selection.

A comparison of psychological functioning in couples undergoing frozen-thawed embryo replacement in various stages of treatment using the Mean Affect Adjective Check List (MAACL).

PURPOSE: The objectives were to identify the stage(s) of frozen embryo replacement cycle where the couples are most vulnerable to psychological dysfunction. Assessment was performed by using the Mean Affect Adjective Check-List (MAACL). METHODS: Thirty couples completed the MAACL questionnaire at the following stages: (a) pretreatment (visit 1), (b) before embryo transfer (visit 2), and (c) before pregnancy test (visit 3). Each partner had to complete a separate questionnaire set. RESULTS: For both partners, the depression score for visit 3 was significantly higher and the sensation seeking and positive affect scores were significantly lower than the corresponding scores for earlier visits. Anxiety scores were similar for all visits. For men, the hostility scores were significantly higher between visits 1 and 2 while in women the same was reported between visits 3 and 2. CONCLUSIONS: Psychological counselling should be targeted at couples especially after embryo transfer. MAACL is a useful method for measuring psychological dysfunction in these couples.

The administration of the GnRH antagonist, cetrorelix, to ooctye donors simplifies oocyte donation.

BACKGROUND: We report our experience on the efficacy of a new regimen of the GnRH antagonist, cetrorelix, and recombinant FSH, Gonal-F, for controlled ovarian stimulation in a donor oocyte programme. METHODS AND RESULTS: Six oocyte donors were commenced on Gonal-F (150 IU) and two on Gonal-F 225 IU daily on day 4 together with cetrorelix 0.25 mg daily on day 8 until the day of administration of hCG. Six premenopausal recipients were down-regulated with intranasal Nafarelin 400 micro g twice daily; two women with premature menopause did not require down-regulation for synchronization between donor and recipient cycles. The median (range) of oocytes retrieved and the median (range) fertilization rates were 7 (3-13) and 50% (0-71%) respectively. With the exception of a recipient who had failed fertilization, seven recipients had two embryos transferred. The median (range) number of days of ovarian stimulation, cetrorelix administration and number of Gonal-F ampoules administered for ovarian stimulation were 9 (7-12) days, 5 (3-8) and 18 (14-24) respectively. The clinical pregnancy rate per cycle was 50% (4/8) and one of the latter women miscarried at eight weeks gestation. Three women (37.3%) had full term deliveries. CONCLUSION: This preliminary study has shown that using a combination of cetrorelix and Gonal-F resulted in a high pregnancy rate, reduced the duration of treatment for the donor and simplified oocyte donation.

A prospective randomized clinical trial comparing 150 IU and 225 IU of recombinant follicle-stimulating hormone (Gonal-F*) in a fixed-dose regimen for controlled ovarian stimulation in in vitro fertilization treatment.

OBJECTIVE: To compare fixed daily doses of the recombinant FSH (rFSH) Gonal-F (150 IU vs. 225 IU) for ovarian stimulation in IVF-ET. DESIGN: Single-center prospective, randomized study. Assisted conception unit of a university hospital. One hundred twenty-four women aged 23-41 years participated in the study. Exclusion criteria were as follows: FSH of >10 IU/L, polycystic ovarian syndrome, one ovary or previous ovarian surgery, previous poor response to ovarian stimulation, or ovarian hyperstimulation syndrome (OHSS). INTERVENTION(S): Randomized to commence 150 IU or 225 IU of Gonal-F per day without dose alterations during treatment. MAIN OUTCOME MEASURE(S): Number of oocytes retrieved and total rFSH dose. RESULT(S): More oocytes were retrieved in women aged or=33 years), the number of oocytes retrieved in the two groups were similar. No significant differences were found for fertilization rate, number of embryos formed and cryopreserved, and pregnancy rates between the two groups. The total rFSH dose used was higher in the 225-IU group (2,595.0 +/- 510.0 vs. 1,897.5 +/- 457.5 IU). The cancellation rate due to insufficient ovarian response was higher in the 150-IU group (15.0% vs. 3.3%). All cases of ovarian hyperstimulation syndrome (n = 4) occurred in the 225-IU group. CONCLUSION(S): Two hundred twenty-five IU is more effective than 150 IU in younger women but requires a higher total dose of Gonal-F. The use of 225 IU in older women did not result in a higher oocyte yield, suggesting that 225 IU of rFSH does not compensate for the age-related decline in the number of follicles available for stimulation.

Regulation of 11beta-hydroxysteroid dehydrogenase type 1 gene expression in human ovarian surface epithelial cells by interleukin-1.

BACKGROUND: Local modulation of 11beta-hydroxysteroid dehydrogenase (11betaHSD) activity, to promote increased availability of anti-inflammatory glucocorticoids, is proposed as a compensatory response to inflammatory stimuli. Human 11betaHSD type 1 (11betaHSD1) is principally an 11-oxoreductase that reversibly reduces cortisone to cortisol. METHODS: Since ovulation is an acute inflammatory process, we examined the influence of pro-inflammatory cytokines on expression of 11betaHSD1 mRNA and metabolism of cortisone to cortisol by human ovarian surface epithelium (HOSE) in vitro. RESULTS: Northern analysis showed an approximately 1.5 kb-sized 11betaHSD1 mRNA transcript in total RNA that was up-regulated approximately 3-fold by interleukin (IL)-1alpha (0.5 ng/ml) at 24 h. By real-time RT-PCR, induction of 11betaHSD1 mRNA by IL-1alpha was measurable at 6 h and maximal at 12 h. Primary HOSE cell cultures also showed low-level 11-oxoreductase activity that was stimulated time- and dose-dependently by IL-1alpha and IL-1beta. The 11betaHSD1 mRNA and 11-oxoreductase responses to 0.5 ng/ILalpha were both suppressed by IL-1 receptor antagonist (25 ng/ml). CONCLUSIONS: Cultured HOSE cells express IL-1-responsive 11betaHSD1 and 11-oxoreductase activity mRNA in vitro. An 11betaHSD1-catalysed increase in anti-inflammatory glucocorticoid activity caused by pro-inflammatory cytokines could contribute to the local resolution of inflammation during ovulation.

Second trimester medical abortion with mifepristone and gemeprost: a review of 956 cases.

The treatment outcomes of 956 women undergoing second trimester termination of pregnancy with mifepristone and gemeprost were studied. The median gestational age was 16 weeks (range: 12-24 weeks). All women were treated with 200 mg mifepristone orally, followed 36 h later with 1 mg vaginal gemeprost administered every 6 h to a maximum of 4 doses in the first 24 h. A second course of 1 mg vaginal gemeprost was given 3-hourly in the next 12 h, if abortion had not occurred. Overall, 96.4% and 98.8% of the women aborted within 24 and 36 h, respectively. The median induction-to-abortion interval was 7.8 h (range: 0.5-109.9 h). The induction-abortion interval was longer in nulliparous women and women with a gestation age 17 weeks or above. Surgical evacuation of the uterus was performed in 11.5% of women for incomplete abortion or retained placenta. More multiparous women (16.7%) required surgical evacuation of uterus than did nulliparous women (7.3%; p <0.001). Ten (0.1%) women failed to abort with gemeprost and required other methods for abortion. In conclusion, a combination of mifepristone and gemeprost is a safe, effective, and noninvasive method of medical abortion for second trimester pregnancy.

Development-related increase in cortisol biosynthesis by human granulosa cells.

Antiinflammatory mechanisms are important in ovulation and may be regulated by cortisol (F). We previously showed that after administration of human (h)CG for ovulation induction, luteinized granulosa cells (LGC) abundantly express 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) messenger RNA but not 11betaHSD type 2 (11betaHSD2) messenger RNA. 11ssHSD1 is responsible for the reversible formation of antiinflammatory F from its inactive precursor cortisone (E), whereas 11betaHSD2 unidirectionally converts F to E through 11-oxidation. This pattern of gene expression predicts that LGC from periovulatory follicles would show increased activation of E to F, compared with granulosa cells from immature follicles (IGC), and that follicular fluid concentrations of E and F would alter accordingly. To test this hypothesis, we isolated IGC, thecal cells (TC), and follicular fluid, from ovaries of cyclic women, removed during surgery for benign gynecological disease. LGC and follicular fluid were aspirated from periovulatory follicles, 35 h after hCG injection, in patients undergoing in vitro fertilization treatment. In an 11betaHSD assay based on interconversion of tritiated E and F by cell suspensions in vitro, IGC (% conversion, 0.6 +/- 0.4, mean +/- SEM) and collagenase-dispersed TC (0.2 +/- 0.1%) were unable to convert E to F, whereas LGC (36.3 +/- 3.7%) were highly efficient at this reaction. Immature granulosa cells, LGC, and (to a lesser extent) TC were all able to convert F to E. Correspondingly, follicular fluid concentrations of total F and F:E ratios were significantly higher in periovulatory follicles, compared with immature follicles. Culturing IGC for 48 h in the presence of hFSH resulted in increased 11betaHSD1 reductase activity, paralleling stimulation of estrogen (aromatase activity) and progesterone biosynthesis. Similar treatment with hLH did not influence 11betaHSD1 reductase activity, except in a patient with more mature IGC, which also showed a significant increase in E-to-F conversion, as well as progesterone synthesis in response to hLH. These data confirm that 11betaHSD activity in the human ovary is developmentally regulated and gonadotropin responsive, favoring metabolism of F to E in immature follicles and E to F in periovulatory follicles. Increased formation of F by LGC in periovulatory follicles is consistent with an antiinflammatory function for this glucocorticoid at ovulation.

Routine antenatal screening for syphilis in Lothian: a study of the results 1988 to 1994.

A retrospective study was carried out of the cases of positive syphilis serology detected by routine antenatal screening within Edinburgh (and surrounding district) over the six years 1988 to 1994. The study demonstrated a low incidence of syphilis with only 15 pregnancies in 58,445 screened. In eight cases serology and history were suggestive of late latent syphilis and in the remainder of previous infection which had been treated. All women were delivered of liveborn infants at term without stigmata of congenital syphilis. Lack of identifiable risk factors in women with positive serology suggests that routine rather than selective screening should continue.

Effects of daily low dose mifepristone on endometrial maturation and proliferation.

Following an ovulatory control cycle, six women took 2 mg of mifepristone daily for 30 days. Endometrial biopsies were collected in the control cycle between 7 and 11 days after the plasma luteinizing hormone (LH) surge and on the corresponding day of the treatment cycle (days 19-28). In order to investigate the effects of unopposed oestrogen on the endometrium, persistent proliferative endometrium was obtained from six women with anovulatory infertility due to polycystic ovarian syndrome (PCOS) on a similar cycle day (days 21-23) following a progestogen-induced withdrawal bleed. Endometrium was evaluated for histology and immunolocalization of oestrogen receptors (ER), progesterone receptors (PR) and the cell proliferation markers [proliferating cell nuclear antigen (PCNA) and Ki67]. Treatment with mifepristone inhibited ovulation in four of the six subjects. In the two subjects in whom ovulation did occur, secretory transformation was delayed, suggesting that successful implantation of a blastocyst would be unlikely. In subjects who remained anovulatory during treatment, the histology and pattern of steroid receptor expression was similar to proliferative phase endometrium. In women with PCOS, mitoses and intense immunostaining for ER, PR and cell proliferation markers were observed in both glands and stroma. Although PCNA and Ki67 immunostaining were also present in mifepristone-treated endometrium from subjects who did not ovulate, there were no mitoses and significantly less ER immunostaining in spite of exposure to unopposed oestrogen for a similar duration. Since PCNA and Ki67 detect cells throughout all stages of the cell cycle this would suggest that mifepristone might affect the entry of cells into the mitotic phase of the cell cycle and, therefore, might prevent endometrial hyperplasia. These findings add further evidence to support the contraceptive potential and antiproliferative activity of daily low dose mifepristone.

A randomised study of two doses of gemeprost in combination with mifepristone for induction of abortion in the second trimester of pregnancy.

Two regimens of the prostaglandin E1 analogue, gemeprost, in combination with mifepristone were compared in a randomised trial for termination of pregnancy between 12-19 weeks. Thirty-six hours after treatment with 200 mg mifepristone, women were allocated at random to receive either 4 x 1 mg (Group I) or 4 x 0.5 mg (Group II) gemeprost by vaginal pessary every 6 hours (n = 50 in each group). If abortion had not occurred after 24 h, 5 x 1 mg of gemeprost was administered every 3 h to both groups of women. Although the median abortion interval was slightly shorter in the 1 mg group (7.8 h vs. 8.4 h, p = 0.5), the cumulative abortion rates at 24 h were similar (98% vs. 96%). Women in Group I required significantly more gemeprost to induce abortion than Group II (p < 0.0001). Parous women in both groups required significantly less of the prostaglandin to induce abortion. In Group II, the median abortion interval was significantly longer in primigravidae than multigravidae (9.5 h vs. 6.1 h; p < 0.02). There were no significant differences between the groups in the incidence of vomiting, diarrhoea or the request for analgesia. The results suggest that in parous women, the dose of gemeprost can be reduced to 0.5 mg every 6 h within the first 24 h without loss of clinical efficacy.

PIP: Two regimens of prostaglandin E1 analogue, gemeprost, in combination with mifepristone were compared in a randomized trial for termination of pregnancy at 12-19 weeks. 100 women requesting second trimester abortion were recruited at the Gynecological Department of the Edinburgh Royal Infirmary, Scotland. The women were given a single oral dose of 200 mg mifepristone in the medical abortion unit and allowed home. 36 hours after treatment with 200 mg mifepristone, women were allocated at random to receive either 4 x 1 mg (Group I) or 4 x 0.5 mg (Group II) gemeprost by vaginal pessary every 6 hours (n = 50 m each group). If abortion had not occurred after 24 hours, 5 x 1 mg of gemeprost was administered every 3 hours in both groups of women. Although the median abortion interval was slightly shorter in the 1 mg group (7.8 vs. 8.4 hours, p = 0.5), the cumulative abortion rates at 24 hours were similar (98% vs. 96%). Women in Group I required significantly more gemeprost to induce abortion than those in Group II (p 0.0001). Parous women in both groups required significantly less of the prostaglandin to induce abortion. Primigravidae took longer to abort than multigravidae, although the difference only reached statistical significance in Group II (median 9.5 hours vs. 6.1 hours; p 0.02). The women in Group II required a lower dose of gemeprost to complete the abortion than those in Group I (median 1 mg vs. 2 mg; p 0.0001). There were no significant differences between the groups in the incidence of vomiting, diarrhea or the request for analgesia. Surgical evacuation of the uterus because of retained or incomplete placenta was required in approximately 1/5 of women in each group. One woman in Group II required blood transfusion because of a retained placenta after expulsion of the fetus. The results suggest that in parous women the dose of gemeprost can be reduced to 0.5 mg every 6 hours within the first 24 hours without loss of clinical efficacy.

Effect of daily low dose mifepristone on the ovarian cycle and on dynamics of follicle growth.

BACKGROUND AND OBJECTIVE: The antiprogestin mifepristone has been shown to disrupt folliculogenesis and endometrial maturation and, therefore, has the potential to be used as a novel form of contraception. The purpose of this study was to investigate further the effects of daily administration of a low dose of mifepristone (2mg) on the ovarian cycle and on the dynamics of follicle growth. SUBJECTS: Six healthy female volunteers were given 2mg mifepristone daily for 30 days following an ovulatory control cycle. MEASUREMENTS: Follicle growth was monitored with transvaginal ultrasonography and hormonal measurements in blood and urine were used to monitor effects on the ovarian cycle. In addition, concentrations of cortisol and ACTH in serum were measured to assess the effects of mifepristone on the pituitary-adrenal axis. RESULTS: Treatment with mifepristone retarded the follicular growth rate in all women (P = 0.01). Ovulation was inhibited in 4 of 6 subjects and appeared to be mediated through an effect on the hypothalamo-pituitary axis, as no surge of FSH or LH occurred. In these subjects the dominant follicle continued to grow and developed into a persistent follicle. In two cases the persistent follicle remained functional and ovulation occurred soon after stopping treatment. In the remaining two subjects, the dominant follicle developed into a non-functioning cyst ( > 30 mm) which persisted for one month after the end of the post-treatment cycle. In the two subjects who ovulated, the LH surge was delayed by 6 and 7 days but was followed by a luteal phase of normal length. There was no significant change in the concentration of ACTH or cortisol suggesting that treatment with mifepristone in this dose has little if any effect on the pituitary-adrenal axis. CONCLUSION: These findings add further evidence to support the contraceptive potential of mifepristone through effects on follicular development and on the menstrual cycle.

PIP: The Centre for Reproductive Biology at the University of Edinburgh, Scotland, recruited six healthy, regularly menstruating women aged 29-36 to a study designed to determine the effects of daily administration of 2 mg mifepristone on the dynamics of follicle growth. The women took a placebo every day during the first menstrual cycle, mifepristone every day, and then a placebo daily for the follow-up cycle. Transvaginal ultrasonography monitored follicle growth. Hormone measurements in the blood and urine as well as pelvic ultrasound monitored the activity of the pituitary-ovarian axis. During the control cycles, all the women had normal ovulation. During the treatment cycle, three patterns of follicle growth emerged: delayed ovulation (2 cases), persistent functional follicle (2 cases), and persistent non-functional cyst (2 cases). Four women did not ovulate during the treatment cycle. In these women, there was no surge of follicle stimulating hormone (FSH) or luteinizing hormone (LH). The dominant follicle still grew and became a persistent follicle. In two of these women, ovulation occurred soon after discontinuation of mifepristone. In the other two women, the dominant follicle became a non-functional cyst of greater than 30 mm in size, which remained for one month after the end of the last control cycle. Mifepristone slowed follicular growth in all women by 5.3 days on average (p = 0.01). It also slowed endometrial growth by 4 days on average (p = 0.04). At the end of both treatment and control cycles, however, the thickness of the endometrium was essentially the same. In the two women who did ovulate, the LH surge took place 6-7 days later than the control cycle, but the length of subsequent luteal phase was normal. Since there was no sizable change in the level of ACTH or cortisol, mifepristone at this low dose has limited influence on the pituitary-adrenal axis. These findings indicate that daily administration of 2 mg mifepristone does not consistently suppress ovulation.