Achievement of pregnancy three times in the same patient during luteal GnRH agonist administration.

Gonadotrophin-releasing hormone agonist (GnRHa) administration from the mid-luteal phase onwards is considered the gold standard of ovarian stimulation for IVF treatment. It might, however, coincide with an implanting spontaneous pregnancy. Concerns have therefore been raised with regard to the evolution of the resulting pregnancies and long-term outcome of the children born. The current case report describes the achievement of three pregnancies in the same patient during luteal administration of GnRHa. One pregnancy ended in spontaneous abortion and the other two resulted in the delivery of two female infants. The children have so far been followed for 3.5 and 7 years. The physical examination of both children was unremarkable. However, the older child has recently been diagnosed with attention deficit hyperactivity disorder and dyslexia.

Prolongation of the follicular phase in in vitro fertilization results in a lower ongoing pregnancy rate in cycles stimulated with recombinant follicle-stimulating hormone and gonadotropin-releasing hormone antagonists.

OBJECTIVE: To assess the effect of altering the timing of hCG administration on ongoing pregnancy rates in patients stimulated with recombinant FSH (rec-FSH) and GnRH antagonists for IVF. DESIGN: Prospective, randomized, controlled trial. SETTING: Tertiary referral center. PATIENT(S): Four hundred thirteen patients undergoing IVF. INTERVENTION(S): Rec-FSH stimulation starting on day 2 of the cycle combined with daily GnRH antagonist starting on day 6 of stimulation. Patients were randomized to receive 10000 IU of hCG either as soon as at least three follicles were >or=17 mm on ultrasound (early-hCG group, 208 patients) or 2 days later after this criterion was met (late-hCG group, 205 patients). MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate. RESULT(S): Fertilization rates and number and quality of embryos transferred did not differ between the two groups. However, a significantly lower ongoing pregnancy rate was present in the late-hCG as compared with the early-hCG group (25.0% vs. 35.6%, respectively). CONCLUSION(S): Prolongation of the follicular phase in patients stimulated with rec-FSH and GnRH antagonists for IVF does not affect oocyte or embryo quality but is associated with a significantly lower ongoing pregnancy rate.

Exogenous luteinizing hormone activity may influence the treatment outcome in in vitro fertilization but not in intracytoplasmic sperm injection cycles.

Additional analysis of a multinational, open-label, randomized study comparing highly purified hMG and recombinant FSH in a long protocol revealed that LH activity might favorably influence pregnancy outcome in IVF cycles.

Quintuplet pregnancy following transfer of two blastocysts: Case report.

A 36-year-old single woman presented at the out-patient clinic in March 2000 requesting donor insemination. Between May 2000 and May 2001 she underwent six cycles of intrauterine insemination with donor sperm after clomiphene citrate stimulation without achieving a pregnancy. In January 2002, ICSI was performed; two embryos were transferred on day 3 and a dizygotic bichorionic pregnancy was achieved, which ended in a miscarriage at 21 weeks of gestation. After a second unsuccessful ICSI attempt in which a single embryo transfer was performed, she embarked upon her third attempt in March 2003 at 39 years of age. Two blastocysts were transferred after ICSI, resulting in a quintuplet gestation consisting of a monochorionic biamniotic pregnancy and a monochorionic triamniotic pregnancy. The current case report indicates that monozygotic pregnancies consisting of both twins and triplets are possible after treatment by assisted reproductive technologies. An association between extended culture, manipulation of the zona pellucida, ovarian stimulation and occurrence of monozygotic pregnancies has been suggested by retrospective studies. However, in order to identify more reliably predictive factors for the occurrence of monozygotic pregnancies, it is necessary to perform prospective trials.

Initiation of gonadotropin-releasing hormone antagonist on day 1 as compared to day 6 of stimulation: effect on hormonal levels and follicular development in in vitro fertilization cycles.

The objective of the present study was to assess the effect of altering the timing of GnRH antagonist initiation on the hormonal environment and follicular development in in vitro fertilization cycles. Sixty women undergoing in vitro fertilization participated in a prospective randomized controlled trial. Patients were stimulated with a fixed dose of 200 IU recombinant FSH, starting on d 2 of the cycle, and with GnRH-antagonist, starting either on d 1 (n = 30) or on d 6 of stimulation (n = 30). A significantly lower exposure to LH (P < 0.001) and estradiol (P < 0.001) during the follicular phase was observed in the d-1 group, compared with the d-6 group of antagonist administration. No differences in follicular development were seen between the two groups on either d 6 of stimulation or on the day of human chorionic gonadotropin administration. Similar fertilization rates, implantation rates, and ongoing pregnancy rates per transfer were, in addition, present between the two groups compared. In conclusion, administration of GnRH antagonist on d 1 (compared with d 6) of stimulation is associated with a lower exposure to LH and estradiol, which does not seem to affect follicular development.

Reproductive outcome of polycystic ovarian syndrome patients treated with GnRH antagonists and recombinant FSH for IVF/ICSI.

The purpose of this prospective study was to assess the reproductive outcome of patients with polycystic ovarian syndrome (PCOS) treated by in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) with recombinant FSH (rFSH) and gonadotrophin releasing hormone (GnRH) antagonists. One hundred and ten patients were evaluated. The starting dose of rFSH was 100 IU in 67 women with body mass index (BMI) 29 kg/m(2). GnRH antagonist was started by the detection of a follicle of a 15mm in ultrasound scan. A significantly lower ongoing pregnancy rate per oocyte retrieval (25.6% versus 46.7%, P = 0.04) and a higher occurrence of ovarian hyperstimulation syndrome (16.3% versus 3.0%, P = 0.03) was observed in the group of patients with BMI >29 kg/m(2) as compared with the group of patients with BMI 29 kg/m(2) in whom stimulation is initiated with 200 IU of rFSH as compared with PCOS patients with BMI

Relationship between LH and oestradiol in IVF cycles before GnRH antagonist initiation.

The objective of this prospective study was to assess the relationship of LH and oestradiol on day 7 of the cycle in patients stimulated with recombinant FSH (rec-FSH) for IVF before initiation of gonadotrophin-releasing hormone (GnRH) antagonist. One hundred and forty-six women treated for IVF using GnRH antagonists for premature LH rise suppression were stimulated with 150 IU of rec-FSH from day 2 to day 6 of the cycle. On cycle day 7, LH concentrations (median 1.8, range 0.1-7.51) were positively associated with oestradiol concentrations on the same day by multiple regression analysis controlling for patient's age, concentrations of FSH and LH on cycle day 2, FSH concentrations on cycle day 7 and follicular index on cycle day 7. In conclusion, the higher the endogenous unsuppressed LH concentrations on day 7 of the cycle after 5 days of stimulation with rec-FSH for IVF, the higher the serum oestradiol concentrations on the same day.

Comparison of transfers to Fallopian tubes or uterus after ICSI.

The aim of this study was to compare the implantation rate of tubal-replaced microinjected oocytes (MIFT) versus conventional day 2 intrauterine embryo transfer in patients undergoing intracytoplasmic sperm injection (ICSI). Sixty-three patients in need of ICSI, between 18 and 37 years of age with normal menstrual cycles and fewer than four previous ICSI attempts, were randomized between April 1999 and December 2001. In the MIFT group, up to three micro-injected oocytes were transferred laparoscopically 4 h after microinjection. In the ICSI-embryo transfer group, up to three cleaving embryos were replaced into the uterine cavity 48 h after insemination. Fifty-nine patients reached the stage of oocyte retrieval; 31 patients had a day 2 embryo transfer and 28 patients had MIFT. The ongoing clinical pregnancy and implantation rate (i.e. the total number of gestational sacs with fetal heartbeat divided by the total number of transferred embryos or micro-injected oocytes) was 35 and 24% in the ICSI-embryo transfer group and 29 and 11% in the MIFT group respectively. In conclusion, this study shows a significant decrease in implantation rate in the MIFT group (P < 0.05). In this group of patients there seems to be no advantage to tubal replacement of micro-injected oocytes.

The impact of LH serum concentration on the clinical outcome of IVF cycles in patients receiving two regimens of clomiphene citrate/gonadotrophin/0.25 mg cetrorelix.

Clomiphene citrate treatment with the association of gonadotrophins and the GnRH antagonist cetrorelix 0.25mg was analysed in two different stimulation protocols for IVF. In protocol I, 18 patients were sequentially stimulated with clomiphene citrate and gonadotrophins. In protocol II, 28 patients started the gonadotrophin injections during the clomiphene citrate administration. LH values significantly dropped after the first 0.25 mg cetrorelix injection in both protocols. A total of 22% and 7% of cycles were cancelled in protocols I and II, respectively, because of poor follicular development. The clinical pregnancy rate following embryo transfer was 18.1% in protocol I and 29.1% in protocol II. In two (11.1%) cycles stimulated according to protocol I and in eight (28.5%) cycles from protocol II, premature LH surges occurred. In patients with premature LH surge, significantly fewer metaphase II oocytes were obtained. The clinical pregnancy rate following embryo transfer was 12.5% in patients with surge compared with 29.6% in patients without. LH values were lower before HCG injection in patients who achieved pregnancy in the study cycle. In conclusion, sequential clomiphene citrate and gonadotrophin administration is not recommended for clomiphene citrate/gonadotrophin/cetrorelix 0.25 cycles. Cetrorelix 0.25 mg/day was associated with a high incidence of premature LH surges and premature LH surges were associated with an adverse cycle outcome.

Exposure to high levels of luteinizing hormone and estradiol in the early follicular phase of gonadotropin-releasing hormone antagonist cycles is associated with a reduced chance of pregnancy.

OBJECTIVE: To compare ongoing implantation rates under two different GnRH antagonist protocols. DESIGN: Randomized controlled trial. SETTING: Tertiary referral center. PATIENT(S): One hundred eleven women undergoing ovarian stimulation for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). INTERVENTION(S): Ovarian stimulation with 150 IU recombinant-FSH (rec-FSH) starting on day 2 of the cycle and GnRH antagonist starting either on day 6 of stimulation (fixed group) or when a follicle of > or = 15 mm was present after at least 5 days of stimulation (flexible group). In the flexible group, the rec-FSH dose was increased to 250 IU when the antagonist was initiated. MAIN OUTCOME MEASURE(S): Ongoing implantation and pregnancy rate. RESULT(S): In patients with no follicle of > or = 15 mm present on day 6 of stimulation, a significantly lower ongoing implantation rate was observed if the flexible scheme was applied as compared with the fixed scheme of administration (8.8% vs. 23.9%, respectively). Exposure of the genital tract to LH or E2 from initiation of stimulation to antagonist administration was able to distinguish between pregnant and nonpregnant patients in the population studied. CONCLUSION(S): High exposure of the genital tract to LH and E2 in the early follicular phase is associated with a reduced chance of pregnancy in cycles stimulated with recombinant FSH and GnRH antagonist for IVF/ICSI.

Human oocytes reversibly arrested in prophase I by phosphodiesterase type 3 inhibitor in vitro.

This study addresses the role of cAMP hydrolytic isoenzyme phosphodiesterase type 3 (PDE 3) modulation on human oocyte maturation in vitro. Presence of phosphodiesterase type 3 A (PDE 3A) mRNA was confirmed in human germinal vesicle-stage (GV) oocytes. Making use of a selective PDE 3 inhibitor, Org 9935 (10 microM), oocytes retrieved from immature follicles were arrested in prophase I with a high efficiency for up to 72 h. Cumulus oocyte complexes (COCs) were retrieved in the follicular phase of the cycle before or after exposure to endogenous LH or hCG administration in vivo and randomly distributed into maturation medium with or without the PDE 3 inhibitor. Previous exposure of small follicles to LH activity in vivo had no influence on the arresting capacity of the PDE 3 inhibitor. Reversal from pharmacological arrest leads to a progression through meiosis in a normal time frame with formation of a well-aligned metaphase plate. Ultrastructure analysis of COC derived from follicles between 8 and 12 mm showed that the induced extension of prophase I arrest in vitro resulted in cytoplasm changes but not in apparent nuclear changes during culture.

An open, randomized single-centre study to compare the efficacy and convenience of follitropin beta administered by a pen device with follitropin alpha administered by a conventional syringe in women undergoing ovarian stimulation for IVF/ICSI.

BACKGROUND: A pen device, similar to an insulin pen, has been recently marketed for the administration of follitropin beta in cartridges. A randomized controlled trial was performed to compare the efficacy and convenience of this pen device delivering follitropin beta with a conventional syringe delivering follitropin alpha. METHODS: A total of 200 patients needing IVF/ICSI treatment and willing to self-inject were enrolled in the study. All subjects had ovarian stimulation according to a long protocol and were randomized to the pen or the conventional syringe group during down-regulation by means of a computer-generated randomization list using random numbers. Patients were asked to fill in a daily local tolerance book after each injection. On the day of hCG the patients scored a Visual Analogue Scale (VAS) for pain and convenience. RESULTS: The average duration, total dose of recombinant FSH and number of cumulus oocyte complexes retrieved were 10.8/12.0 days (P = 0.001), 1880/2226 IU (P < 0.001) and 15.2/13.1 respectively in the pen device and conventional syringe groups; the presence of pain after the daily injection was significantly higher in the conventional syringe group (P = 0.027); the visual analogue scale score was similar for pain but significantly more convenient for the pen device (P < 0.001). The live birth rate per embryo transfer was 32.9 and 34.4% respectively in the pen device and conventional syringe groups. CONCLUSIONS: Self-injection with the pen device is safe and easy, more convenient and less painful for the patient, requires less FSH and shortens the treatment duration.

Endometrial integrin expression in the early luteal phase in natural and stimulated cycles for in vitro fertilization.

OBJECTIVE: To investigate the effect of ovarian stimulation on integrin expression in the early luteal phase. STUDY DESIGN: Seven endometrial biopsies were taken 2 days after the oocyte retrieval from stimulated cycles for IVF and 23 from natural cycles, 2 days after ovulation. RESULT: Endometrium was in-phase in 22/23 and 7/7 biopsies from the natural and stimulated cycles, respectively. Integrins alpha(1) and alpha(4) were simultaneously positive in 43.4% from the natural and in all (100%) the stimulated cycles (P<0.03). On the day of the endometrial biopsy, progesterone serum values were higher in the stimulated cycles (55.2+/-9.5 microg/l versus 8.5+/-3.8 microg/l) (P<0.001). HSCORE value was significantly higher in stimulated cycles for both integrins. CONCLUSION: Endometrial integrin expression is more consistently present in the early luteal phase in stimulated cycles than in natural cycles and this may be related to the higher serum progesterone concentration and/or the more advanced endometrial histological features.

Rescue IVF and coasting with the use of a GnRH antagonist after ovulation induction.

The major risks of exogenous gonadotrophin therapy for ovulation induction in a patient with polycystic ovaries (PCO) are multiple pregnancies and ovarian hyperstimulation syndrome (OHSS). This case report describes a 23-year-old patient, who was referred to the Centre for Reproductive Medicine in Brussels because of a high risk of developing OHSS and rising LH following ovulation induction with a low-dose step-up protocol using gonadotrophins. After counselling the patient, the decision was made to perform a rescue IVF cycle. The patient was first coasted with 0.25 mg ganirelix; the serum oestradiol concentrations decreased and the LH peak was successfully suppressed. No OHSS occurred. An ongoing twin pregnancy was achieved after the transfer of two embryos. This case report demonstrates the feasibility of coasting with LH-releasing hormone (LHRH) antagonists (0.25 mg ganirelix) and the usefulness of the antagonists for ovulation induction cycles in patients who need rescue IVF.

Effect of ovarian stimulation with recombinant follicle-stimulating hormone, gonadotropin releasing hormone antagonists, and human chorionic gonadotropin on endometrial maturation on the day of oocyte pick-up.

OBJECTIVE: To assess the effect of ovarian stimulation with recombinant FSH, GnRH antagonists, and hCG on endometrial maturation on the day of oocyte pick-up. DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENT(S): Fifty-five women undergoing controlled ovarian hyperstimulation for IVF/intracytoplasmic sperm injection (ICSI). INTERVENTION(S): [1] Ovarian stimulation with recombinant FSH, starting on day 2 of the cycle and GnRH antagonist, starting after a median of 6 days of recombinant FSH stimulation (range, 5-12 days); [2] hCG administration for ovulation induction; and [3] aspirational biopsy of endometrium at oocyte pick-up. MAIN OUTCOME MEASURE(S): Endometrial histology at oocyte pick-up by Noyes criteria. RESULT(S): Advancement of endometrial maturation (2.5 +/- 0.1 days) as compared to the expected chronological date was observed in all antagonist cycles at oocyte retrieval. Endometrial advancement at oocyte pick-up increased in line with values of LH at initiation of stimulation and the duration of recombinant FSH treatment before the antagonist was started. CONCLUSION(S): The higher the values of LH at initiation of stimulation and the longer the duration of recombinant FSH treatment before the antagonist is started, the more advanced the endometrial maturation at oocyte pick-up.

Intracytoplasmic sperm injection versus in vitro fertilization: a randomized controlled trial and a meta-analysis of the literature.

OBJECTIVE: To compare ICSI with IVF using two insemination concentrations in moderate male infertility and to compare these data with other randomized controlled trials (RCTs). DESIGN: Prospective, randomized, controlled trial and meta-analysis. SETTING: University-based tertiary referral center. PATIENT(S): Seventy-three couples undergoing ART. INTERVENTION(S): In one IVF group a standard insemination concentration of 0.2 x 10(6)/mL was used, whereas in the other group a high insemination concentration (HIC) of 0.8 x 10(6)/mL was used. Each protocol was compared with ICSI on sibling oocytes. MAIN OUTCOME MEASURE(S): Fertilization, fertilization failure, and embryonic development. RESULT(S): The overall fertilization rate was significantly lower after standard IVF than after ICSI: 37.4% vs. 64.3%. Where HIC IVF was used, the overall fertilization rate was not significantly different from that after ICSI: 59.6% vs. 67.6%. Eight randomized controlled trials were selected and reviewed together with the present randomized controlled trial by meta-analysis. The risk ratio for an oocyte to become fertilized was 1.9 (95% confidence interval of 1.4 to 2.5) in favor of ICSI, and 3.1 ICSI cycles may be needed to avoid one complete fertilization failure after conventional IVF (95% CI of 1.7 to 12.4). CONCLUSION(S): The data from this study and the meta-analysis show that ICSI is a more efficient technique in terms of fertilization, but not in comparison with HIC IVF.

Effect of clomiphene citrate on follicular and luteal phase luteinizing hormone concentrations in in vitro fertilization cycles stimulated with gonadotropins and gonadotropin-releasing hormone antagonist.

OBJECTIVE: To investigate the effect that clomiphene citrate exerts on luteinizing hormone (LH) concentrations in gonadotropin/gonadotropin-releasing hormone (GnRH) antagonist cycles. DESIGN: Retrospective analysis. SETTING: Tertiary referral center. PATIENT(S): Two groups of patients undergoing in vitro fertilization (IVF) were compared. In group I, 20 patients were stimulated with clomiphene citrate (CC) in combination with gonadotropins and 0.25 mg of Cetrorelix (ASTA Medica AG; Frankfurt am Main, Germany) and in group II, 20 patients were stimulated with gonadotropins and 0.25 mg of Cetrorelix. INTERVENTION(S): Blood sampling was performed in the late follicular, periovulatory, early, mid, and late luteal phases. MAIN OUTCOME MEASURE(S): Luteinizing hormone (LH), estradiol, and progesterone. RESULT(S): LH levels were significantly higher in group I than in group II on all the days studied. Progesterone serum concentrations were significantly higher in group II in the early luteal phase, but not in the follicular or the middle and late luteal phases. CONCLUSION(S): LH concentrations are significantly higher in the follicular and luteal phases in cycles stimulated with CC, despite GnRH antagonist administration. This observation might have implications for the dose of GnRH antagonist needed to suppress LH in the follicular phase and questions the need for luteal-phase supplementation in cycles in which CC was used.