Dose-finding study of Leuplin depot for prevention of premature luteinizing hormone surge during controlled ovarian stimulation: a pilot study in intrauterine insemination treatment.

OBJECTIVE: The standard dose of depot gonadotropin releasing hormone agonist (GnRHa) may be too much to prevent premature luteinizing hormone (LH) surge in controlled ovarian stimulation (COS). The purpose of this study was to find out the minimal effective dose of Leuplin depot to prevent premature LH surge in patients undergoing intrauterine insemination (IUI). MATERIALS AND METHODS: From January 2006 to December 2007, unexplained infertile patients who were going to undergo IUI were recruited into the study. They were assigned sequentially to one of the following treatment groups. The first 50 patients received the 1/3-dose of Leuplin depot in the midluteal phase of the cycle preceding COS. If no premature LH surge occurred in the 50 patients, the study was continued with 1/4-dose of Leuplin depot in the subsequent 50 patients. Similarly, if no premature LH surge occurred with 1/4 dose, the study was continued with 1/5-dose of Leuplin depot in the following 50 patients. Ovarian stimulation was started with human menopausal gonadotropin (hMG) at 112.5 IU/d after downregulation, then IUI was performed 36 hours after human chorionic gonadotropin (hCG) injection. RESULTS: Premature LH surge was effectively prevented with 1/3-dose and 1/4-dose of Leuplin depot. Premature LH surge occurred in three of the 50 patients (6%) in the 1/5-dose group. The patients in the 1/4-dose group received a significantly lower amount of hMG and fewer days of COS, compared with the 1/3-dose group. CONCLUSION: The 1/4 dose of Leuplin depot is the minimal effective dose to prevent premature LH surge. Further trial is worthwhile to compare the reducing dose Leuplin depot and daily low-dose leuprolide in in vitro fertilization (IVF) programs.

Bacterial colonization with balloon uterine stent placement in the uterus for 30 days: a randomized controlled clinical trial.

OBJECTIVE: To assess bacterial colonization following balloon uterine stent placement in the uterus for 30 days. DESIGN: Prospective randomized controlled study. SETTING: Tertiary medical center. PATIENT(S): Sixty-eight women scheduled for hysteroscopy. INTERVENTION(S): Women who were undergoing hysteroscopic surgery were randomly assigned to receive a balloon uterine stent or not. Before starting surgery, the uterine cavity was swabbed for bacterial culture. The device was placed in the uterus after surgery in the stent group. After 30 days, the stent was removed and sent for culture and the uterine cavity also swabbed and cultured. The uterine cavities of the control patients were swabbed before and 30 days after surgery. MAIN OUTCOME MEASURE(S): The primary outcome was the incidence of bacterial colonization of the uterus. Secondary outcomes were pain intensity and species of colonizing bacteria. RESULT(S): Excluding eight women, 30 women in each group were included in this analysis. In the stent group, three women (10.0%) demonstrated bacterial colonization before surgery compared with nine women (30.0%) after 30 days. In the control group, four (13.3%) and ten (33.3%) women had microorganisms detected in the uterus before and after 30 days after surgery, respectively. In neither group did the percentage of women with uterine microorganisms increase significantly after 30 days. The percentages of women with uterine bacterial colonization before and 30 days after surgery were similar between both groups. CONCLUSION(S): Balloon uterine stents may be placed after surgery for up to 30 days without increasing bacterial colonization. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (www.clinicaltrials.gov) NCT01167296.

Comparison of Quinn's Advantage fertilization medium and tissue culture medium 199 for in vitro maturation of oocytes.

OBJECTIVE: The purpose of the study was to compare the Quinn's Advantage fertilization medium (Q1) and the tissue culture medium 199 (TCM199) for in vitro maturation (IVM) of oocytes and ammonium production during IVM. MATERIALS AND METHODS: The immature murine oocytes were randomly added into Q1 and TCM199. Ammonium concentrations were measured at the start and after 18 hours of IVM, and the mature oocytes were fertilized and cultured into blastocysts. The blastocysts were then stained for inner cell mass (ICM) and trophectoderm. RESULTS: The maturation rate was higher in Q1 than in TCM199 (85.7% vs. 76.6%, p = 0.024). The fertilization and blastocyst rates were slightly higher in Q1, but not significant. Differential staining of the blastocysts showed slightly higher ICM ratio in the blastocysts derived from Q1. Mean ammonium concentrations in Q1 and TCM199 at Time 0 were 184.9 and 339.2 µg/dL, respectively (p = 0.05), and after 18 hours of IVM were 268.7 and 443.6 µg/dL, respectively (p = 0.045). Addition of ammonium chloride into Q1 adversely affects IVM. CONCLUSION: Q1 is superior to TCM199 in terms of oocyte maturation, which may be due to lower ammonium concentration.

Combination of cabergoline and embryo cryopreservation after GnRH agonist triggering prevents OHSS in patients with extremely high estradiol levels--a retrospective study.

PURPOSE: Embryo cryopreservation after triggering oocyte maturation with GnRH agonist (GnRHa) in GnRH antagonist protocols has been proposed to prevent ovarian hyperstimulation syndrome (OHSS). However, a small percentage of patients still developed severe OHSS. The purpose of the study was to investigate the efficacy of preventing OHSS in patients at very high risk when cabergoline was given in addition to elective cryopreservation after GnRHa triggering. METHODS: This is a retrospective observational study. The patients were stimulated with GnRH antagonist protocol. When serum E2 concentration was >6,000 pg/ml and there were more than 20 follicles ≥11 mm on the day of final oocyte maturation, GnRHa was used to trigger oocyte maturation. Cabergoline was given to augment the effect of preventing OHSS. The embryos were electively cryopreserved by vitrification and thawed in subsequent cycles. The primary outcome measure was the incidence of severe OHSS. The secondary outcome measure was the clinical pregnancy rate in the first frozen-thawed embryo transfer cycle. RESULTS: One hundred and ten patients underwent 110 stimulated cycles were included for analysis. No patients developed moderate/severe OHSS. Mean E2 concentration on the day of final oocyte maturation was 7,873 pg/ml, and an average of 22.7 oocytes was obtained from each patient. One hundred and ten thawing cycles were performed, resulting in 69 clinical pregnancies (62.7 %). CONCLUSIONS: Combining cabergoline and embryo cryopreservation after GnRHa triggering in GnRH antagonist protocol could prevent OHSS in patients at very high risk.

Clinical outcome according to timing of cabergoline initiation for prevention of OHSS: a randomized controlled trial.

Cabergoline, a dopamine receptor-2 agonist, is suggested to prevent ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation. The aim of this study was to evaluate the influence of different timing of cabergoline administration on clinical outcome among patients at risk of developing OHSS. Among infertile women undergoing IVF treatment at risk of developing OHSS, 206 were enrolled in this study. The subjects were randomly allocated into two groups, i.e. the study group (n=100) receiving cabergoline beginning on the day of human chorionic gonadotrophin (HCG) injection and the control group (n=100) receiving cabergoline starting on the day of oocyte retrieval. Oocyte metaphase-II rate, fertilization rate, clinical outcome and incidence of severe OHSS were compared between the two groups. There were no significant differences in oocyte metaphase-II rate (0.86 ± 0.16 versus 0.85 ± 0.15) or fertilization rate (0.79 ± 0.22 versus 0.76 ± 0.20) or in the incidence of OHSS between two groups. Similarly, there were no significant differences in implantation or clinical pregnancy rate between the two groups. Cabergoline can be administered as soon as HCG injection to prevent early OHSS, without adverse effects on oocyte maturation, fertilization rate and clinical outcome.

Effect of incubation with different concentrations and durations of FSH for in-vitro maturation of murine oocytes.

The purpose of the study was to evaluate whether a lower concentration of FSH or 2-h incubation with FSH would improve the outcome of in-vitro maturation of oocytes. The immature oocytes were obtained from FVB mice, and were allocated to four groups and incubated in the maturation media for 24 h. The maturation media were supplemented with 10 mIU/ml FSH for 24 h (group 1), 10 mIU/ml FSH for 2 h (group 2), 75 mIU/ml FSH for 24 h (group 3) or 75 mIU/ml FSH for 2 h (group 4). In each group, half of the in-vitro-matured oocytes were fertilized and cultured to blastocysts and the remaining matured oocytes were analysed for growth differentiation factor (GDF)-9 and bone morphogenetic protein (BMP)-15 mRNA to assess the oocyte quality. The maturation rates and oocyte BMP-15 mRNA concentrations were similar among the four groups. The GDF-9 mRNA concentrations were similar in group 2 and group 4. The fertilization and blastocyst rates were higher in groups 2 and 4 than in groups 1 and 3. It is concluded that 2-h incubation with FSH is better than 24-h incubation in terms of the fertilization rate and blastocyst development.

Characteristics of progesterone changes in women with subtle progesterone rise in recombinant follicle-stimulating hormone and gonadotropin-releasing hormone antagonist cycle.

BACKGROUND: To assess the characteristics of progesterone (Prog) changes in women with a subtle Prog rise in recombinant follicle-stimulating hormone (r-FSH) and GnRH antagonist cycles. METHODS: We enrolled 233 patients undergoing controlled ovarian hyperstimulation with r-FSH and GnRH antagonist for IVF or ICSI. A subtle Prog rise 1 day before hCG administration was defined as a Prog value of > or =1.2 ng/ml. RESULTS: 100 of 233 cycles (42.9%) showed a subtle Prog rise in this study. The mean serum Prog levels and area under curve (AUC) in the group with Prog > or =1.2 ng/ml was significantly higher than that in the Prog <1.2 ng/ml group on cycle day 8 (1.17 +/- 0.4 and 0.80 +/- 0.3 ng/ml, respectively, for Prog level, p = 0.003; 571 +/- 123 and 763 +/- 250 for AUC, p = 0.001), and remained significantly higher until the day of hCG administration. Moreover, 55% of the patients on cycle day 9, 65% on cycle day 10, 75% on cycle day 11 and 85% on cycle day 12 in the Prog > or =1.2 ng/ml group have a serum Prog level of > or =1.2 ng/ml. CONCLUSION: A subtle Prog rise may occur as early as cycle day 8 in r-FSH/GnRH antagonist cycles.

Safety and efficacy of mixing cetrorelix with follitropin alfa: a randomized study.

OBJECTIVE: To assess the safety and efficacy of mixing cetrorelix with follitropin alfa (rFSH) in assisted reproductive technology. DESIGN: Prospective, randomized study. SETTING: An IVF center in a teaching hospital. PATIENT(S): One hundred forty patients undergoing intracytoplasmic sperm injection were randomized into mixed (M) or separate (S) injection groups. INTERVENTION(S): In the M group, rFSH and cetrorelix were mixed immediately before administration, whereas in the S group, rFSH and cetrorelix were administered separately. MAIN OUTCOME MEASURE(S): The primary efficacy end point was the incidence of premature LH surge. The secondary efficacy endpoints included estradiol levels on the day of hCG injection, numbers of oocytes obtained, implantation, and ongoing pregnancy rates. The safety endpoints included ovarian hyperstimulation syndrome, and adverse events related to injections including local tolerability. RESULT(S): Excluding eight patients who dropped out of the study, there were 66 patients in each group for analysis. Patients in the M group received significantly fewer injections than patients in the S group (9.1 vs. 13.9). Other outcome parameters, including incidences of premature LH surge, numbers of oocytes retrieved, fertilization, implantation, and ongoing pregnancy rates were similar between the two groups. CONCLUSION(S): Cetrorelix and rFSH can be mixed together without compromising their reported safety and efficacy. This observation is in line with the reported safety and efficacy profile of the products listed in their current package inserts.

Laminaria tent vs misoprostol for cervical priming before hysteroscopy: Randomized study.

STUDY OBJECTIVE: To compare the efficacy of laminaria tents and orally administered misoprostol in priming the cervix before operative hysteroscopy. DESIGN: Randomized, controlled study (Canadian Task Force classification I). SETTING: Tertiary medical center. PATIENTS: One hundred twenty premenopausal women who underwent operative hysteroscopy between March 2005 and January 2007. INTERVENTION: The women were randomized to receive a laminaria tent or misoprostol for cervical priming. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were postpriming cervical width insofar as size of Hegar dilators and need for cervical dilation. The secondary outcomes were adverse effects from the priming methods. Postpriming cervical width was greater in the laminaria group but not significantly different from that in the misoprostol group. However, cervical dilation before hysteroscopy was required in more patients in the misoprostol group. Nausea, vomiting, diarrhea, and bleeding were more common in the misoprostol group, and the incidences of chills and headache were similar between the 2 groups. CONCLUSION: Laminaria tents are superior to oral misoprostol insofar as less need for cervical dilation and fewer adverse effects.

Conservative treatment of cervico-isthmic heterotopic pregnancy by fine needle aspiration for selective embryo reduction.

An unusual case of a heterotopic cervico-isthmic pregnancy after IVF treatment occurred in a 34-year-old woman. Transvaginal ultrasound-guided aspiration of the gestational sac for embryo reduction was safely used to manage the pregnancy and preserve the intrauterine fetus.

Effect of a lower-dose cetrorelix acetate protocol on in-vitro fertilization outcome.

OBJECTIVE: To determine whether a low initial dosage of cetrorelix acetate could prevent a premature luteinizing hormone (LH) surge in women undergoing controlled ovarian stimulation. METHOD: Treatment with a recombinant follicle stimulating hormone was started on Day 3 of the menstrual cycle, and 0.125 mg of cetrorelix was injected daily from Day 5 of the ovarian stimulation until the diameter of the dominant follicle reached at least 16 mm. The dosage was then doubled and maintained at 0.250 mg/day until the day before the injection of human chorionic gonadotropin. RESULT: There was a significant decrease in serum LH concentration 1 day after doubling the cetrorelix dosage, and the LH concentration remained low during the follicular phase. Clinical pregnancy occurred in 18 women (42.8%), with 2 intrauterine fetal deaths before the 12th week. CONCLUSION: Increasing the cetrorelix dosage from 0.125 to 0.250 mg/day when the follicular size is appropriate can prevent a premature LH surge.

Subtle progesterone rise in the single-dose gonadotropin-releasing hormone antagonist (cetrorelix) stimulation protocol in patients undergoing in vitro fertilization or intracytoplasmic sperm injection cycles.

A subtle rise in serum progesterone during the late follicular phase in patients undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles is a frequent event that can decrease implantation and pregnancy rates in controlled ovarian hyperstimulation (COH) protocols that use a gonadotropin-releasing hormone (GnRH) antagonist. The aim of the present study was to evaluate the prevalence and effect of the subtle progesterone rise during COH with single-dose GnRH antagonist in combination with clomiphene citrate (CC) and human menopausal gonadotropins (hMG) in IVF or ICSI cycles. Ninety-five women undergoing COH with CC, hMG and a single 2.5 mg dose of the GnRH antagonist, cetrorelix, were enrolled in the study. Patients were grouped according to serum progesterone level on the day of human chorionic gonadotropin (hCG) administration (P < 1.2 ng/ml or P >/= 1.2 ng/ml). The incidence of a subtle progesterone rise was 54.7% (52/95). The group with P >/= 1.2 ng/ml had significantly higher serum levels of luteinizing hormone (p = 0.002) and estradiol (p < 0.001) on the day of hCG injection than the group with P < 1.2 ng/ml, and more oocytes were retrieved (p = 0.001). However, there was no significant difference in fertilization, clinical pregnancy or implantation rate between the two groups. In conclusion, a subtle progesterone rise during the late follicular phase is common but not associated with pregnancy outcome.

Application of GnRH antagonist in combination with clomiphene citrate and hMG for patients with exaggerated ovarian response in previous IVF/ICSI cycles.

PURPOSE: To investigate if the combination of clomiphene citrate, hMG, and cetrorelix (CC/hMG/cetrorelix protocol) can be applied to patients who had excessive response to GnRHa long protocol. METHODS: Fifty patients who coasted and failed to conceive in their first cycles stimulated with GnRHa long protocol were stimulated with CC/hMG/cetrorelix protocol. The peak serum estradiol levels, the need of coasting and prolonged coasting (>/=4 days), and the incidences of OHSS were compared. RESULTS: The peak estradiol level was significantly lower with CC/hMG/cetrorelix protocol compared to GnRHa long protocol. With CC/hMG/cetrorelix protocol, only four patients (8%) needed coasting and no one coasted >/=4 days. In contrast, in the first cycles, 11 patients (22%) needed coasting >/=4 days. The incidence of moderate OHSS was significantly lower with CC/hMG/cetrorelix protocol. CONCLUSIONS: The CC/hMG/cetrorelix protocol is an acceptable alternative protocol for patients who had excessive response to GnRHa long protocol.

Spontaneous hemoperitoneum in pregnancy from a ruptured superficial uterine vessel.

A 31-year-old multipara woman pregnant at gestational age 32+ weeks with twins encountered hemoperitoneum resulting from superficial uterine vessel rupture during tocolytic course. The initial presentations were unspecific and sonographic examination was negative. Later the aggravated symptoms led to an impression of abruption placentae and emergent cesarean section was performed. A superficial venous bleeder was located on the posterior uterine wall and the internal bleeding was up to 3 L. Maternal and fetal outcome were good. Hemoperitoneum during pregnancy is rare but life-threatening to both mother and fetus, and it mimics placenta abruption in many ways. However, by careful investigations with cardiotocogram and bedside echo, they are quite distinguishable. Aggressive fluid replacement and immediate surgical intervention after rapid diagnosis provides the best prognosis.

Midtrimester maternal serum inhibin A levels after multifetal pregnancy reduction.

OBJECTIVE: To investigate the relationship between the maternal serum inhibin A concentrations and the number of fetuses. Further, the maternal serum inhibin A levels for twin pregnancies and multiple pregnancies reduced to twins in the second trimester were compared. METHODS: Three groups of women with pregnancies following in vitro fertilization and embryo transfer were recruited for this study. Groups 1, 2 and 3 included 20 singleton pregnancies, 37 twin pregnancies, and 35 multifetal pregnancies, respectively. In group 3, multifetal reduction was performed during 10-12 weeks of gestation. Blood samples were obtained longitudinally at 10th, 12th, 15th and 18th week of gestation. RESULTS: There was a significant association between the number of fetuses and maternal plasma inhibin A prior to multifetal reduction. The inhibin A levels were not significantly different between twin and multifetal reduced twin pregnancies at 15th and 18th weeks of gestation. CONCLUSION: In multifetal reduction to twin pregnancies, the maternal serum levels of inhibin A decrease to the level of twin pregnancies during the second trimester. Therefore, inhibin A may be effectively used as a marker for Down syndrome screening in cases of twin pregnancy following multifetal reduction.

Is a lower dose of cetrorelix acetate effective for prevention of LH surge during controlled ovarian hyperstimulation?

PURPOSE: This study was performed to evaluate whether a lower dose (0.2 mg) of cetrorelix would prevent premature LH surge in patients undergoing controlled ovarian hyperstimulation. METHODS: Controlled ovarian hyperstimulation was carried out in 45 patients, starting on menstrual cycle day 3 with recombinant FSH (r-FSH), and a cetrorelix of 0.2 mg was administered from day 5 evening of ovarian stimulation until the day before hCG injection. RESULTS: There was a statistically significant decrease in serum LH level one day after the first cetrorelix injection and on the day of hCG administration. Serum LH concentrations were maintained constantly low during the follicular phase with no premature LH surge occurring in any of the patients. Clinical pregnancy was achieved for 18 women (40%), with one of these experiencing intrauterine fetal death before 12 week' gestation. CONCLUSION: This study demonstrates that a daily dose of cetrorelix 0.2 mg is able to prevent premature LH surge.

Comparison of outcome of clomiphene citrate/human menopausal gonadotropin/cetrorelix protocol and buserelin long protocol--a randomized study.

This study evaluates the efficacy of a stimulation protocol with clomiphene citrate (CC)/human menopausal gonadotropin (hMG)/cetrorelix and its effects on oocyte quality and endometrium. One hundred and twenty couples with male-factor infertility who were about to undergo their first intracytoplasmic sperm injection cycles were randomized into two groups. Sixty women were stimulated with the CC/hMG/cetrorelix protocol (cetrorelix group) and 60 received the buserelin long protocol (buserelin group). Fewer oocytes were recovered in the cetrorelix group than in the buserelin group (mean +/- standard deviation (SD): 11.1 +/- 4.0 vs. 17.3 +/- 5.8, p < 0.001); however, the percentages of metaphase II, metaphase I and germinal vesicle oocytes were similar between the two groups. Serum estradiol level was significantly lower in the cetrorelix than in the buserelin group (mean +/- SD: 2600.58 +/- 1189.11 vs. 3293.46 +/- 1221.49 pg/ml, p = 0.006), but the endometrial thickness was similar. The implantation rates (19.2% vs. 17.7%) and the pregnancy rates (41.7% vs. 40.0%) were similar between groups. The ampoules (mean +/- SD: 18.9 +/- 3.0 vs. 38.9 +/- 12.2, p < 0.001) and injections (mean +/- SD: 6.8 +/- 1.1 vs. 15.7 +/- 3.1, p < 0.001) of gonadotropin used were significantly lower in the cetrorelix group than in the buserelin group. No patients in either group developed a premature luteinizing hormone surge. The present study found no statistically significant difference between the two treatment modalities with regard to pregnancy rates.

IVF versus ICSI in sibling oocytes from patients with polycystic ovarian syndrome: a randomized controlled trial.

BACKGROUND: This study compares the fertilization rate and embryonic development of oocytes randomly inseminated by conventional IVF or ICSI in patients with polycystic ovarian syndrome (PCOS) and normozoospermic semen during IVF cycles. METHODS: Sibling oocytes were randomized to be inseminated either by ICSI or IVF. Fertilization rate (two pronuclei/COC), day 2 embryonic morphology and rate of development were assessed. RESULTS: A total of 1089 cumulus-oocyte complexes (COC) were collected in 60 cycles (mean+/-SD, 18.2 +/- 7.2). Totals of 541 and 548 COC were inseminated by IVF and ICSI respectively, with a significantly higher fertilization rate in the ICSI group (ICSI versus IVF, 72.3 +/- 15.5 versus 44.8 +/- 25.1%). No fertilization failure occurred in the group of oocytes inseminated by ICSI, whereas the COC in nine patients (15%) inseminated by IVF had complete fertilization failure. The day 2 embryonic morphology and rate of development were not different regardless of the insemination method. CONCLUSIONS: Our results suggested that another randomized controlled study, randomizing patients instead of sibling oocytes, should be undertaken to compare the pregnancy rate per started cycle and to see whether ICSI should be performed on all, or at least on a portion of, oocytes for patients with PCOS undergoing IVF cycles.

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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The Diane/cetrorelix protocol has a similar pregnancy outcome to the GnRH agonist long protocol for women with PCOS undergoing IVF treatment.