Programmed ovulation induction and oocyte retrieval for in vitro fertilization. Cetrorelix in an oral contraceptive-pretreated stimulation cycle compared with buserelin in IVF/ICSI patients treated with r-hFSH: a randomized, multicentre, phase IIIb study. Effect of an oral contraceptive pill on follicular development in IVF/ICSI patients receiving a GnRH antagonist: a randomized study. Progestogen therapy and prevention of functional ovarian cysts during pituitary desensitisation with GnRH agonists. The hormonal flare-up following gonadotrophin-releasing hormone agonist administration is influenced by a progestogen pretreatment. A combination of norethindrone acetate and leuprolide acetate blocks the gonadotrophin-releasing hormone agonistic response and minimizes cyst formation during ovarian stimulation. Ovarian stimulation by concomitant administration of cetrorelix acetate and HMG following Diane-35 pre-treatment for patients with polycystic ovary syndrome: a prospective randomized study. Administration of progestogens to hasten pituitary desensitization after the use of gonadotropin-releasing hormone agonist in in vitro fertilization--a prospective randomized study. Effects of pretreatment with an oral contraceptive on the time required to achieve pituitary suppression with gonadotropin-releasing hormone analogues and on subsequent implantation and pregnancy rates. [Application of GnRH-antagonist to IVF-ET for patients with poor ovarian response]. Effects of oral contraceptive, synthetic progestogen or natural estrogen pre-treatments on the hormonal profile and the antral follicle cohort before GnRH antagonist protocol. A comparative randomized trial to assess the impact of oral contraceptive pretreatment on follicular growth and hormone profiles in GnRH antagonist-treated patients.
Forty-two patients underwent programmed ovulation induction for oocyte retrieval. They were treated in the preceding cycles with a progestagen, ethynodiol diacetate, at a dose of 2 mg twice daily. Two groups were defined based upon the stimulation protocol: Group A1 was stimulated with clomiphene citrate and human menopausal gonadotropin (hMG), and Group A2 with follicle-stimulating hormone (FSH) and hMG. They were compared to two randomized control groups of patients who received the same induction but were classically monitored. There was a high proportion of spontaneous ovulations in the programmed group (8/42) compared to the nonprogrammed group (0/42). There was a nonsignificant difference in the number of oocytes obtained or embryos replaced per cycle. Four pregnancies were obtained in the programmed group (24% per transfer), against 10 in the nonprogrammed patients (32% per transfer). The results of this method seem to be better using FSH for ovulation stimulation and a verification of the serum estradiol on the day of induction with human chorionic gonadotropin (hCG) and the following day (semiprogrammed method). The aim of this study was to assess the non-inferiority of an oral contraceptive (OC)-pretreated cetrorelix regimen and a buserelin regimen in IVF/ICSI patients treated with r-hFSH in terms of total number of oocytes retrieved.
                Multicentre, randomized study. One hundred and eighty two patients were randomized to receive cetrorelix with OC pretreatment (n = 91) or to receive buserelin (n = 91). The cetrorelix group started with daily OCs on cycle day 5 and continued for 21-28 days. Cetrorelix (0.25 mg) was given daily from stimulation day 6 up to and including the day of r-hCG administration. The buserelin group started with buserelin (500 microg/day) for at least 10 days until down-regulation was achieved, after which the dose was reduced to daily 200 microg up to and including the day of r-hCG administration. r-hFSH was started in both groups on a Friday, in the cetrorelix group 5 days after the last OC pill intake. Both regimens were followed by a standard IVF or ICSI procedure. The primary efficacy endpoint was the number of oocytes retrieved per patient.
                Number of oocytes, cancellation rates, r-hFSH requirements, number of oocyte retrievals during the weekend or public holiday and number of pregnancies were similar in both groups. Both treatment regimens were well tolerated.
                Cetrorelix pretreated with OCs resulted in similar number of oocytes retrieved compared with a long buserelin protocol. Both regimens were well tolerated and allowed scheduling of the oocyte retrieval, with only small number of retrievals falling on a weekend or public holiday. This randomized controlled study compared the effectiveness of a gonadotrophin releasing hormone (GnRH) antagonist protocol with or without oral contraceptive (OC) pretreatment on the number of oocytes retrieved in IVF or intracytoplasmic sperm injection (ICSI) patients. Sixty-four patients were randomized to start recombinant human FSH (r-hFSH) on day 2 or 3 after OC withdrawal (OC group) or on day 2 of a natural cycle (control group). From stimulation day 6 onwards, all patients were treated with daily (0.5 mg/ml) GnRH antagonist (Antide). OC pretreatment resulted in significantly lower starting concentrations of FSH, LH and oestradiol (P < 0.001) and a thinner endometrium (P < 0.0001). In the early stimulation period, fewer large follicles were found after OC pretreatment, leading to a significantly extended stimulation period (11.6 versus 8.7 days, P < 0.0001) with more follicles on the day of recombinant human chorionic gonadotrophin administration (15.4 versus 12.5, P = 0.02) and more oocytes retrieved (13.5 versus 10.2, P < 0.001) as compared with the control group. GnRH antagonist regimen, pretreated with OC, prevented the early endogenous FSH rise and improved follicular homogeneity, resulting in more oocytes. As a consequence of the extended treatment period, more rhFSH was required. nan In a short-term protocol, the influence of progestogen pretreatment upon the oestradiol flare-up (delta E2) induced by gonadotrophin-releasing hormone agonist (GnRHa) was assessed in relation to in-vitro fertilization (IVF) outcome in 90 cycles programmed (n = 52) or not (n = 38) by norethisterone (10 mg/day for 12-20 days). Patients pretreated by progestogen had a significantly lower delta E2 value than patients without pretreatment (delta E2 = 26 +/- 5 versus 61 +/- 8 pg/ml, P = 0.003). It could be related to a lower gonadotrophic response for luteinizing hormone (LH) (delta LH = 9 +/- 0.8 versus 14.5 +/- 2.2 IU/l, P = 0.01). The IVF outcome (final oestradiol, number of oocytes or embryos) was similar in both groups and delta E2 was well correlated with these final parameters in each group. A significant rise in serum progesterone was observed only in patients without pretreatment (delta P = 1.1 +/- 0.2 versus 0.1 +/- 0.1 ng/ml, P < 0.0001). Thus norethisterone pretreatment decreases the oestradiol flare-up and prevents the early increase of progesterone (by avoiding some rescue of the corpus luteum or some luteinization of small developing follicles) but does not influence the outcome of the IVF cycle. In clinical practice, evaluation of the hormonal flare-up for predicting IVF outcome must take into account any pretreatment prescription. A protocol utilizing both leuprolide acetate (LA) and norethindrone acetate (NETA) in subjects undergoing ovarian suppression prior to follicle aspiration proved more effective than LA alone in reducing the incidence of ovarian cyst formation without affecting clinical outcome. Patients (n = 105) undergoing ovarian stimulation followed by follicle aspiration and in-vitro fertilization (IVF) were prospectively randomized and studied. Study measures included ovarian suppression days, days of human menopausal gonadotrophin (HMG) stimulation, serum oestradiol concentrations, number of cycles developing de novo cysts (>15 mm), number of induced flare responses (day 8 oestradiol >=50 pg/ml), number of office visits, total dose exogenous gonadotrophins, number oocytes retrieved, and clinical pregnancy and delivery rates per retrieval. Patients undergoing IVF received either LA alone (n = 58; controls) or LA and NETA (n = 47; study group) for the first 8 days of their cycle. Results comparing NETA/LA versus LA demonstrated: serum oestradiol 20.7 +/- 3.9 versus 57.3 +/- 9.4 pg/ml respectively on day 8 of ovarian suppression (P P < 0.01); and only three individuals (6.4%) using NETA/LA developed ovarian cysts >15 mm compared to 15 (25.9%) controls (P < 0.01). No differences were observed for days of stimulation, peak oestradiol attained, total dosage of exogenous gonadotrophins, or number of aspirated oocytes. Neither were there differences in the clinical pregnancy (26.8 versus 22.6%) nor in delivery rates (19.5 versus 20. 8%). We conclude that the addition of NETA to LA enhances ovarian suppression and lessens ovarian cyst formation, thereby significantly decreasing the overall cost per cycle. Patients with polycystic ovary syndrome (PCOS) may need a longer period of pituitary downregulation to suppress the elevated serum LH and androgen levels effectively during IVF treatment using the GnRH agonist long protocol. We proposed a stimulation protocol incorporating Diane-35 and GnRH antagonist (Diane/cetrorelix protocol) and compared it with the GnRH agonist long protocol for PCOS patients.
                Part I of the study was an observational pilot study to evaluate the hormonal change as a result of the Diane/cetrorelix protocol (n = 26). Part II of the study was a prospective randomized study comparing the Diane/cetrorelix protocol (n = 25) and the GnRH agonist long protocol (n = 24). In the Diane/cetrorelix protocol, patients were pre-treated with three cycles of Diane-35, followed by 0.25 mg of cetrorelix on cycle day 3. From day 4, cetrorelix and gonadotrophin were administered concomitantly until the day of HCG injection.
                Serum LH, estradiol and testosterone levels were suppressed comparably in both protocols at the start of gonadotrophin administration. Serum LH was suppressed at constant levels without a premature LH surge in the Diane/cetrorelix protocol. The clinical results for both protocols were comparable, with significantly fewer days of injection, lower amounts of gonadotrophin used and lower estradiol levels on the day of HCG injection following the Diane/cetrorelix protocol. Furthermore, there was no significant difference in clinical pregnancy outcome between the two stimulation protocols.
                The Diane/cetrorelix protocol has a similar pregnancy outcome to the GnRH agonist long protocol for women with PCOS undergoing IVF treatment. To assess the effect of administration of adjuvant IM progestogen to patients undergoing IVF who were not pituitary desensitized after 14 days of GnRH agonist (GnRH-a) administration.
                Prospective randomized study.
                A tertiary referral center for assisted conception.
                Forty-nine patients undergoing 51 IVF treatment cycles.
                Patients in whom the endometrial thickness was > 5 mm or who had an ovarian cyst > 15 mm after 14 days of GnRH-a administration were recruited if the serum E2 concentration was > 27.24 pg/mL (> 100 pmol/L). Patients in group 1 (n = 22) received a single IM injection of 100 mg P whereas patients in group 2 (n = 29) did not. Patients in both groups continued to receive SC GnRH-a 500 micrograms/d and had serum E2 levels measured every 3 days until the concentrations were < or = 100 pmol/L.
                The number of days of GnRH-a administration from recruitment until serum E2 concentration measured < or = 100 pmol/L, number of cycles with withdrawal bleeding, number of days from recruitment to withdrawal bleeding, total dose of hMG used, number of follicles > 14 mm, number of oocytes, number of embryos, and pregnancy rates per cycle commenced and per ET.
                There were no significant differences in all the above parameters except in the mean number of days from recruitment to onset of withdrawal bleeding, which were 5.33 +/- 0.7 (mean +/- SEM) and 8.62 +/- 1.26 days in groups 1 and 2, respectively. The pregnancy rate per ET was higher in group 1 (38.88%) when compared with group 2 (19.04%). However, this difference was not statistically significant.
                Adjuvant administration of a single IM injection of progestogen hastens the onset of withdrawal bleeding in patients who are not pituitary desensitized after 2 weeks of administration of SC GnRH-a. It does not appear to affect the length of time the serum E2 concentrations take to reach basal levels or to alter the ovarian responsiveness to exogenous gonadotropins. To assess the effect of pretreatment with an oral contraceptive (OC) on ovarian cyst formation during pituitary suppression with buserelin acetate.
                Prospective randomized trial.
                Academic medical center.
                Eighty-three patients who were undergoing IVF-ET treatment.
                Patients in the study group were pretreated with an OC for 14 days starting on the first day of menstruation. The administration of SC buserelin acetate was initiated on the last day of OC administration. Patients in the control group began to receive buserelin acetate on day 2 of menstruation. Hormonal assays and ultrasound scans were performed on the first day of menstruation, and 7, 11, and 14 days after the commencement of buserelin acetate administration. Thereafter, these tests were performed weekly until pituitary suppression was achieved.
                Incidence of cyst formation.
                A cyst developed in 27 patients in the control group (52.9%) and no patients in the study group (odds ratio [OR]=115; 95% confidence interval [CI]=10-617). Patients in the study group achieved pituitary suppression faster (median difference [MD]=7 days; 95% CI=4-14) and required fewer ampules of gonadotropin (MD=10; 95% CI=6-14). They recruited more follicles (MD=3; 95% CI=0-5) and had higher pregnancy rates (37.2% versus 33.3%).
                Pretreatment with an OC abolishes ovarian cyst formation, shortens the time required to achieve pituitary suppression, and decreases gonadotropin requirements without having a negative effect on pregnancy rates. To compare the outcomes achieved by GnRH-antagonist and GnRH-agonist in IVF-ET for patients with poor ovarian responses, and to find out a better protocol for ovulation stimulation.
                (1) Patients with poor ovarian responses were assigned to an experimental (n = 63) and a control group (n = 58), treated respectively with GnRH-Ant and oral contraceptive plus micro-dose GnRH-a (OC + GnRH-a), and comparisons were made of the medication doses, laboratory results and pregnancy outcomes between the two groups. (2) Twenty of the patients were treated first with GnRH-Ant and then with OC + GnRH-a, and the same comparisons were made between the two protocols.
                Between the experimental and the control groups, there were no significant differences in the dose of Gn and number of retrieved oocytes and transplanted embryos (P > 0.05), nor in the pregnancy rate of transplantation cycles (37.29% vs 35.29%). The cycle cancellation rate was lower in the experimental than in the control group (6.35% vs 12.07%), with no statistical difference (P > 0.05). The cycle duration was significantly different between the two groups ([9.65 +/- 1.60] d vs [19.05 +/- 3.94] d) (P < 0.05). As for the comparison of GnRH-Ant with GnRH-a, no significant differences were observed in the dose of Gn and the numbers of retrieved oocytes and transplanted embryos (P > 0.05). GnRH-Ant achieved a higher pregnancy rate of transplantation cycles but a significantly lower cancellation rate than GnRH-a (38.09% vs 17.64% and 0% vs 15%) (P > 0.05 and P < 0.01), respectively. The cycle duration of the former was statistically shorter than that of the latter ([9.91 +/- 2.49] d vs [27.74 +/- 25.39] d) (P < 0.05).
                Compared with micro-dose GnRH-a, GnRH-Ant can shorten the cycle duration and reduce the cancellation rate in IVF-ET for patients with poor response. And for those who have failed to respond to GnRH-a, GnRH-Ant may be tried in another attempt at IVF-ET. Steroid pre-treatments may be useful to program GnRH antagonist IVF/ICSI cycles. This prospective study assessed hormonal and ultrasound data collected during the free period after the discontinuation of three different pre-treatments to provide information on the optimal time interval required before starting stimulation.
                Women were randomized to receive oral contraceptive pill (OCP) [ethinyl estradiol (E(2)) 30 microg + desogestrel 150 microg] (n = 21) or norethisterone 10 mg/day (n = 23) or 17-betaE(2) 4 mg/day (n = 25) or no pre-treatment (n = 24) for one cycle before IVF. Assessments were performed on post-treatment day (PD) 1, 3 and 5, or on spontaneous cycle day (CD) 1 and 3.
                After OCP and progestogen administration, FSH and LH concentrations shifted from strongly suppressed PD1 levels to PD5 values similar to those observed on CD1. Meanwhile, follicle sizes remained small up to PD5. In contrast, estrogen pre-treatment poorly reduced FSH levels on PD1 compared with OCP or progestogen. Consequently, follicle size was more heterogeneous. FSH rebound was maximal on PD3, whereas LH levels were slightly increased up to PD5.
                A 5-day free interval after OCP or progestogen offers the advantages of gonadotrophin recovery and homogeneous follicular cohort, whereas early FSH rebound occurring after estrogen pre-treatment argues for a short free period. This randomized controlled trial was designed to assess the impact of oral contraceptive (OC) scheduling with a GnRH antagonist (ganirelix) regimen on the ovarian response of women undergoing recombinant FSH (rFSH) stimulation for IVF, compared with a non-scheduled ganirelix regimen and a long GnRH agonist (nafarelin) protocol.
                A total of 110 women was treated with an OC and ganirelix, 111 with ganirelix alone and 111 with nafarelin. The OC (containing 30 microg ethinylestradiol/150 microg desogestrel) was taken for 14-28 days and stopped 2 days prior to the start of rFSH treatment. Primary efficiency parameters were the number of cumulus-oocyte complexes (per attempt) and the number of grade 1 or 2 embryos (per attempt).
                In terms of follicular growth and hormone profiles, the OC-scheduled antagonist regimen mimicked the agonist regimen rather than the (non-scheduled) GnRH antagonist regimen. In the OC-scheduled GnRH antagonist group and the nafarelin group (versus the non-scheduled antagonist group), pituitary suppression was more profound at the start of stimulation (P < or = 0.001), there was a slower start of follicular growth (P < or = 0.001), longer stimulation was required (11.7 and 10.3 days respectively versus 9.4; P < or = 0.001), and more rFSH was used (2667 and 2222 IU versus 1966 IU; P < or = 0.001). In the three groups, the number of oocytes was similar (13.1, 12.9 and 11.5 respectively; not significant) as well as the number of good quality embryos (5.1, 5.7 and 5.0 respectively; not significant).
                OC treatment prior to the rFSH/ganirelix regimen can be successfully applied to schedule patients, although more days of stimulation and more rFSH are required than with a non-scheduled GnRH antagonist regimen.
There was evidence of improved pregnancy outcomes with progestogen pre-treatment and poorer pregnancy outcomes with a combined OCP pre-treatment. However, we conclude that major changes in ART protocols should not be made at this time, since the number of overall studies in the subgroups is small and reporting of the major outcomes is inadequate.