Results of in vitro fertilization and embryo transfer by combined long-acting gonadotropin-releasing hormone analog D-Trp-6-luteinizing hormone-releasing hormone and gonadotropins

To avoid cancellation of in vitro fertilization (IVF) because of early luteinization, pituitary suppression by gonadotropin-releasing hormone (GnRH) was carried out in 111 cycles. D-Trp-6-luteinizing hormone-releasing hormone (LH-RH) microcapsules were administered intramuscularly at menstruation and menotropin (hMG) stimulation was started 19 days (mean) later. In 3 cycles (2.7%), only early luteinization occurred. The mean number of oocytes per cycle was 6.7, with a fertilization and cleavage rate of 50 and 95%, respectively. A mean of 3.4 embryos were transferred per cycle. The 111 cycles resulted in 34 clinical pregnancies, 41% per cycle with embryo transfer. The early abortion, multiple pregnancy, and ovarian hyperstimulation rates were 24, 18, and 11%, respectively. It is concluded that D-Trp-6-LH-RH/hMG cycles are associated with a very low occurrence of early luteinization, high number of oocytes and embryos, and a substantial incidence of ovarian hyperstimulation syndrome.     

The impact of the refractory period to gonadotropin therapy in IVF-ET cycles post longacting gonadotropin-releasing hormone (GNRH) analogue.

Sixty-nine women were treated with a long-acting gonadotropin-releasing hormone analogue (GnRHa), D-Trp-6-LH-RH (DTRP6) 3.2 mg (Decapeptyl, Ferring, Kiel, F.R.G.) prior to induction of ovulation for in vitro fertilization (IVF) with human menopausal gonadotropin (hMG; Pergonal; Serono Laboratories, Inc., Randolph MA). Three types of response were noted: Group I (18 patients) responded between days 1-3 of the treatment; Group II (30 patients) responded between days 4-6 of the therapy, and Group III (21 patients) responded after 7 days of treatment. Although a higher number of oocytes were encountered in Group I than in the latter two groups fertilization and clinical pregnancy rates were lower than in Group II (P less than 0.05), respectively, but higher than in Group III (P less than 0.07 and P less than 0.01), respectively. The best results were achieved by Group II patients, while Group III seemed to represent low responders as the number of embryos and pregnancy rate were significantly lower than in the other two groups. It seems that the level of ovarian suppression achieved by GnRH analogue results in a period of refraction of the ovary, and its duration has most probably an effect upon the results of the IVF cycles.     

Ovarian hyperstimulation syndrome following D-Trp-6 luteinizing hormone-releasing hormone microcapsules and menotropin for in vitro fertilization

In 143 cycles of in vitro fertilization the ovarian hyperstimulation syndrome (OHSS) occurred in 12 (8.4%) cycles. Six were in the moderate form and 6 severe. Ovarian stimulation by menotropins was preceded by induction of hypopituitary hypogonadism using D-Trp6-LH-RH microcapsules. The OHSS cycles are characterized by improved ovarian response expressed by the increased serum levels of estradiol, number of follicles, oocytes, embryos and pregnancy rate as compared to cycles with no OHSS. All patients recovered uneventfully. The follicular puncture did not have the suggested protective effect against OHSS. It is suggested that the substantial incidence of OHSS is probably related to the excessive ovarian stimulation not interrupted by early luteinization which is practically abolished by this protocol. The role of the given luteal hCG doses in the genesis of OHSS is questioned.     

The use of gonadotropin-releasing hormone analogs for in vitro fertilization: comparison between the standard form and long-acting formulation of D-Trp-6-luteinizing hormone-releasing hormone

The introduction of luteinizing hormone-releasing hormone (LH-RH) analogs into treatment schemes for the stimulation of ovulation has enabled the authors' in vitro fertilization (IVF) team to overcome two problems; they can now suppress spontaneous LH peaks and program their activity. Two hundred and five IVF cycles were investigated. The agent used was D-Trp-6-LH-RH, either in a sustained release formulation (112 cases, group 1) or in a standard form (93 cases, group 2). The quantity of human menopausal gonadotropin (hMG) necessary for adequate ovarian stimulation was much lower when the standard form of the analog was used. The number of oocytes recovered per puncture was greater in group 1 (7.6 compared with 5.1), but the difference was not significant when considering the number of embryos (2.4 compared with 2.1). The corrected pregnancy rate (with allowance for progressive introduction of freezing from the third embryo onwards) was identical in both groups. The authors conclude that systems in which LH-RH analogs are employed have a clear advantage over the classical treatment with clomiphene citrate/hMG, and that the immediate-action formulation of D-Trp-6-LH-RH is preferable.     

Gonadotropin-releasing hormone agonist improves the efficiency of controlled ovarian hyperstimulation/intrauterine insemination

OBJECTIVE: Leuprolide acetate (LA) has improved the efficiency of human menopausal gonadotropins (hMG) in in vitro fertilization cycles. We hypothesized that the combination of LA/hMG/intrauterine insemination (IUI) would be more efficacious than hMG/IUI cycles. DESIGN: During an 18-month period, all patients completing either a hMG/IUI cycle (group I) or a LA/hMG/IUI cycle (group II) had the characteristics and outcomes of their stimulation cycles assessed. The groups were not prospectively randomized. SETTING: Referral center at a tertiary care hospital. PATIENTS: One hundred twenty three patients in group I completed 219 cycles, and 64 patients in group II completed 102 cycles. Twenty-eight of the patients who failed to conceive with hMG/IUI were advanced to group II. MAIN OUTCOME MEASURES: Pregnancy/IUI is compared between the two groups. RESULTS: Group II demonstrated significantly greater clinical pregnancy/IUI than group I (26.5% and 16.0%, respectively, P less than 0.05), as well as a higher live birth/IUI (21.6% and 12.8%, respectively, P less than 0.05). No difference was present in the rate of fetal wastage or multiple births. CONCLUSIONS: In our patients with recalcitrant infertility, the addition of a gonadotropin-releasing hormone agonist to hMG/IUI improved the pregnancy rate, without increasing the rate of multiple births or fetal wastage.     

The effect of cycle length on the outcome of in vitro fertilization

In order to study the effect of cycle length on the pregnancy rate in an in vitro fertilization and embryo transfer (IVF-ET) program, 173 consecutive patients were divided into short menstrual cycle (mode 26 days or less) and normal cycle (mode 27 days or more) groups. Patients were randomly allocated to one of two treatments, commencing ovarian stimulation with human menopausal gonadotropin (hMG) on either day 2 or day 4 of their cycle. The number of oocytes retrieved and embryos transferred did not differ significantly. The amount of hMG used and day of human chorionic gonadotrophin administration both differed significantly (P less than 0.01) between regimens but was independent of cycle length. Both the clinical pregnancy rate (30.2% versus 9.4%, P less than 0.05) and the number of cleaved embryos giving rise to gestation sacs (16% versus 3.4%, P less than 0.02) was significantly higher in patients with a normal cycle length. Mode cycle length has a significant bearing on the outcome of IVF-ET cycles.     

Lower pregnancy rate with premature luteinization during pituitary suppression with leuprolide acetate

The relationship of the circulating level of progesterone (P) on the day of human chorionic gonadotropin (hCG) injection to occurrence of clinical pregnancy was examined in 133 leuprolide acetate human menopausal gonadotropin (hMG) in vitro fertilization cycles in women having at least three embryos transferred. Progesterone concentrations greater than 0.5 ng/mL were associated with a significantly lower rate of pregnancy (12/59, 20%) compared with less than 0.5 ng/mL (40/74, 54%, P less than 0.005). The higher P cycles were associated with greater patient age and hMG dose, although these relationships appeared to be indirect. Luteinizing hormone (LH) concentrations remained suppressed. Ovarian stimulation may cause excessive luteinization and an adverse cycle outcome even in the presence of low LH levels. Prospective use of P levels may be helpful to determine optimal hCG timing.     

A randomized prospective study on the effect of short and long Buserelin treatment in women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response

Fifty four women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response to stimulation with human menopausal gonadotropins (hMG) participated in this study. They were randomized to receive either gonadotropin releasing hormone agonist (GNRHa), Buserelin, prior to and during induction of ovulation by hMG (Group I—long protocol), or GnRHa starting on the first day of the cycle together with induction of ovulation by hMG (Group II—short protocol). Mean follicular phase serum luteinizing hormone (LH) and progesterone (P) levels were significantly lower in Group I than in Group II (P<0.01). Cancellation rate was significantly lower in Group I than in Group II (P<0.01). The long GNRHa protocol resulted in statistically significant lower cancellation rates, more oocytes per pickup (OPU), more embryos trans-ferred per patient, and a higher pregnancy rate. Significantly more hMG ampoules and more treatments days were required in the long GNRHa protocol. Our data demonstrate that the use of GNRHa prior to and during ovarian stimulation with hMG offers a very good alternative for patients with repetitive unsuccessful IVF cycles due to inadequate response.     

Follitropin-alpha versus human menopausal gonadotropin in an in vitro fertilization program

OBJECTIVE: To compare the efficacy of recombinant FSH and urinary-derived hMG for ovarian stimulation during IVF. DESIGN: Retrospective analysis of data from IVF cycles conducted over 15 months. SETTING: University hospital IVF unit. PATIENT(S): Three hundred twenty-four women undergoing their first to sixth IVF cycle. INTERVENTION(S): After pituitary down-regulation, patients received recombinant FSH or hMG, according to personal choice. After hCG administration, patients underwent oocyte retrieval, oocyte fertilization, and embryo transfer. MAIN OUTCOME MEASURE(S): Implantation rate and clinical ongoing pregnancy rate per oocyte retrieval. RESULT(S): Patients who chose recombinant FSH were slightly younger than those who chose hMG (34.1 vs. 35.1 years, respectively). Although more embryos were transferred in the hMG group (3.6 vs. 3.2), the ongoing pregnancy and implantation rates were significantly higher in the recombinant FSH group (ongoing pregnancy rate, 50.0% vs. 36.2%). CONCLUSION(S): Recombinant FSH is more effective than hMG for ovarian stimulation in IVF cycles. This increased efficacy, which is achieved with fewer ampoules, is likely to offset the higher acquisition costs of recombinant FSH.     

Outcome of in-vitro fertilization and embryo transfer after different regimens of ovarian stimulation

Sixty-eight women with bilateral tubal disease and fertile male partners underwent ovarian stimulation in 187 cycles for IVF after randomization to different ovulation induction regimens. All patients initially received 150 mg clomiphene citrate on days 5-9, this regimen induced sufficient stimulation in a smaller proportion of patients than the two other regimens used subsequently which included clomiphene in combination with human menopausal gonadotrophins (hMG). The fertilization rate was significantly reduced (52.4%) in oocytes collected from cycles stimulated with hMG alone (in a small sub-group of poor responders) compared with a rate of 64.1-66.4% in cycles stimulated with clomiphene alone or in combination with hMG. Embryonic development 44-48 h after insemination was significantly retarded when clomiphene alone was utilized but a higher proportion of fragmented or abnormal embryos was observed after stimulation with hMG alone. In 118 cycles embryo transfer was performed and 20 pregnancies were established, a pregnancy rate of 16.9%. All but two pregnancies were established when two or more embryos were transferred and when the embryos were at the 4-cell or later stage of development. The regimen of clomiphene in combination with 150 i.u. hMG resulted in significantly greater numbers of oocytes recovered and embryos available per patient for transfer than the other two regimens studied.     

The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins.

OBJECTIVE: To assess the outcome of in vitro fertilization and embryo transfer (IVF-ET) in women with refractory polycystic ovarian syndrome (PCOS). DESIGN: Retrospective case series with an age-matched control group. SETTING: Ovulation induction and IVF programs in a tertiary referral center. PATIENTS AND INTERVENTIONS: Nine patients with PCOS who failed standard ovulation induction treatment (clomiphene citrate plus greater than or equal to 6 ovulatory human menopausal gonadotropin [hMG] cycles) underwent 19 cycles of IVF-ET. Forty age-matched tubal factor patients who completed 40 cycles of IVF-ET served as a control group. OUTCOME MEASURES: Demographic features and IVF-ET cycle characteristics were compared using Student's t-test and Fisher's exact test. RESULTS: Cycles of IVF-ET in patients with PCOS were associated with higher estradiol levels (5,222 versus 4,009 pmol/L), lower hMG requirements (15.8 versus 19.6 vials), greater numbers of oocytes (7.6 versus 5.6), and lower fertilization rates (56% versus 75%) compared with tubal factor cycles (P less than 0.05). However, the number of embryos transferred (3.9 versus 4.0) and the clinical pregnancy rate per embryo transfer (24% versus 25%) did not differ significantly between the two groups. CONCLUSION: These results suggest that conception failure after six or more ovulatory hMG cycles in patients with PCOS does not adversely affect subsequent IVF performance.     

Gonadotropins and combined gonadotropin-releasing hormone agonist--gonadotropins protocols in a randomized prospective study

A prospective study was designed to compare cycles stimulated by human menopausal gonadotropin (hMG) (group A) with cycles pretreated with gonadotropin-releasing hormone agonist causing pituitary desensitization followed by hMG stimulation (group B). Three hundred two cycles were randomly allocated to each group. Cancellation rate was 27.2% in group A compared with only 3.3% in group B. Significantly less hMG ampules for a shorter period were needed in group A patients. Lower estradiol and higher luteinizing hormone levels were detected in the hMG group. Patients in group B yielded significantly more oocytes and more embryos per retrieval. A significantly higher pregnancy rate per cycle was obtained in group B (27%) as compared with that of group A (13%). Moderate and severe ovarian hyperstimulation syndrome was significantly more frequent in group B than in group A.     

Outcome of in-vitro fertilization and embryo transfer after different regimens of ovarian stimulation

Summary. Sixty-eight women with bilateral tubal disease and fertile male partners underwent ovarian stimulation in 187 cycles for IVF after randomization to different ovulation induction regimens. All patients initially received 150 mg clomiphene citrate on days 5–9, this regimen induced sufficient stimulation in a smaller proportion of patients than the two other regimens used subsequently which included clomiphene in combination with human menopausal gonadotrophins (hMG). The fertilization rate was significantly reduced (52–4%) in oocytes collected from cycles stimulated with hMG alone (in a small sub-group of poor responders) compared with a rate of 64·1–66·4% in cycles stimulated with clomiphene alone or in combination with hMG. Embryonic development 44–48 h after insemination was significantly retarded when clomiphene alone was utilized but a higher proportion of fragmented or abnormal embryos was observed after stimulation with hMG alone. In 118 cycles embryo transfer was performed and 20 pregnancies were established, a pregnancy rate of 16·9%. All but two pregnancies were established when two or more embryos were transferred and when the embryos were at the 4-cell or later stage of development. The regimen of clomiphene in combination with 150 i.u. hMG resulted in significantly greater numbers of oocytes recovered and embryos available per patient for transfer than the other two regimens studied.     

Ovulation induction by human menopausal gonadotropin with ultrasonic monitoring of the ovarian follicles

One hundred sixteen cycles of human menopausal gonadotropin (hMG) treatment for ovulation induction were studied. The ovarian response to hMG treatment was monitored by the daily determination of serum estradiol (E2) or by daily serum E2 and repeated ultrasonic examination of the ovaries. There were more follicles 18 mm in diameter or larger at the time of human chorionic gonadotropin (hCG) administration in the pregnancy than in the non-pregnancy cycles, and in the hyperstimulated than in the nonhyperstimulated cycles. The ovulatory rate and the pregnancy rate per cycle did not improve with the use of ultrasound. The number of treatment cycles required to achieve pregnancy was less in patients who had ultrasonic examination of the ovarian follicles. These results suggest that ultrasonic examination of the ovarian follicle helps to reduce the number of hMG cycles required to achieve pregnancy. The development of multiple follicles results in more pregnancies. However, the use of ultrasound does not improve the pregnancy rate.     

Pregnancy rate and ovarian hyperstimulation after luteal human chorionic gonadotropin in in vitro fertilization stimulated with gonadotropin-releasing hormone analog and menotropins

The value of luteal phase supplementation with human chorionic gonadotropin (hCG) was assessed after a combined protocol of ovarian stimulation, using a long acting gonadotropin releasing hormone analog (GnRH-a) and human menopausal gonadotropins (hMG), in a randomized prospective study of 36 consecutive cycles in an in vitro fertilization (IVF) program. The patients were allocated on the transfer day to either luteal phase supplementation with hCG (Group A, n = 18) or none (Group B, n = 18). Nine patients of Group A conceived as compared with 3 in Group B. Five patients, all in Group A, developed ovarian hyperstimulation syndrome (OHSS) (3 moderate and 2 severe forms). Analysis of the hormonal profiles disclosed similar progesterone (P), estradiol (E2), and E2/P ratio up to the 6th post ovum pick-up day. Then, E2 and mainly P levels decreased only in Group B resulting in a rising E2/P ratio. These findings stress the importance of luteal support in IVF cycles treated with GnRH-a. In light of the increased risk of OHSS among hCG treated patients, further studies are needed to assess the optimal preparation needed.     

The use of gonadotropin releasing hormone agonist (GnRHa) in good responders undergoing repeat in vitro fertilization/embryo transfer (IVF/ET)

The use of gonadotropin releasing hormone agonists (Gn-RHa) has been shown to improve the response in patients classified as poor responders undergoing ovarian stimulation for in vitro fertilization/embryo transfer (IVF/ET). This study sought to determine whether GnRHa therapy would benefit patients undergoing IVF/ET who had been classified as good responders in prior attempts. Twenty-three patients who had completed a prior IVF/ET attempt but who failed to conceive underwent ovarian stimulation using a combination of GnRHa and human menopausal gonadotropin (hMG). Each patient's prior stimulation served as her control and consisted of clomiphene citrate (CC)/hMG in 18 patients and follicle stimulating hormone (FSH) and/or hMG in 5 patients. The numbers of oocytes retrieved, oocytes fertilized, embryos cleaved, and embryos transferred were all significantly greater in cycles treated with GnRHa/hMG compared to control cycles. The clinical pregnancy rate was 39% and the ongoing pregnancy rate was 26% during the cycle when GnRHa pretreatment was utilized. These data suggest that GnRHa therapy is of benefit even to those patients previously classified as good responders undergoing ovarian stimulation for IVF/ET.Presented at the 45th Annual Meeting of the American Fertility Society, November 1989, San Francisco, California.     

克罗米芬对卵巢储备功能减退患者进行促排卵治疗的有效性研究

目的:研究IVF/ISCI治疗中克罗米芬(CC)用于卵巢储备功能减退(DOR)患者促排卵治疗的效果。方法:回顾性分析年龄<35岁但基础FSH≥12 IU/L,或者年龄≥35岁患者的388个CC联合人绝经期促性腺素(hMG)的促排卵周期全胚行冻融胚胎移植(FET)的治疗结局,所有患者既往有≥1次促排卵治疗失败史。结果:年龄<35岁组,获卵数为4.5±3.1个,有效胚胎数为2.2±1.8个,优质胚胎数为1.6±1.5个,用药时间为8.8±2.0 d。在年龄≥35岁的患者中,获卵数为4.5±2.8个,有效胚胎数为2.2±1.8个,优质胚胎数为1.9±1.6个,用药时间为8.8±1.9 d。FET的临床妊娠率2个年龄组分别为37.8%和36.4%,组间无统计学差异(P>0.05)。结论:对于基础FSH水平高或者年龄≥35岁的DOR患者,CC联合hMG是一种有效的促排卵方案。     

Choice of an ovarian stimulation protocol according to the follicular puncture method in an in vitro fertilization programme

In order to ascertain the adequacy of ovarian stimulation protocols with a type of follicular puncture, 126 women undergoing in vitro fertilization received either combination clomiphene/hMG or hMG alone according to a randomized test protocol. Within both groups patients for whom a pelvic examination was required had laparoscopies, while others had transvaginal ultrasonically guided punctures as far as possible. Clomiphene/hMG was more efficient than hMG alone as assessed from the cleavage rate (68% vs. 54%; p less than 0.01) and the pregnancy per attempt rate (16% vs. 5%; p less than 0.05). Laparoscopic punctures were more efficient than ultrasonically guided punctures (mean number of recovered oocytes: 4.8 +/- 2.6 vs. 3 +/- 2.5; p less than 0.001), but slightly better results were achieved by this latter method in ongoing pregnancy per puncture rate (18% vs. 8%; NS). With ultrasonically guided punctures, stimulation by clomiphene/hMG allowed better oocyte recoveries (3.8 +/- 2.5 vs. 2.3 +/- 1.9, p less than 0.05). Such results constitute an argument for preferential use of the clomiphene/hMG stimulation protocol with ultrasonically guided punctures.     

The prognostic importance of the number of oocytes retrieved and estradiol levels in poor and normal responders in in vitro fertilization (IVF) treatment

A low response to ovarian stimulation in in vitro fertilization poses a unique therapeutic challenge. Gonadotropin-releasing hormone agonists (GnRHa) have been suggested as a modality for treatment of this condition. In this study, we analyzed the results of 880 in vitro fertilization treatment cycles with respect to modality of ovarian stimulation, degree of hormonal response, and number of oocytes retrieved. In patients with estradiol (E ₂ )levels less than 501 pg/ml on the day of human chorionic gonadotropin administration, 27% pregnancy rate was achieved with clomiphene citrate (CC) combined with human menopausal gonadotropin (hMG), compared to 15.1% (P <0.005) with hMG alone and 20.8% (NS) with GnRHa and hMG. Pregnancy rates were not lower in these patients compared to patients with higher estradiol levels in the different stimulation protocols, but pregnancy rates were significantly lower in cycles during which three or fewer oocytes were retrieved, compared to those in which four or more oocytes were retrieved (10.8 vs 23.8%; P <0.0005). In low-retrieval cycles pregnancy rates actually decreased with increasing levels of estradiol. Our results indicate that the number of oocytes retrieved is a better prognostic parameter than E ₂ levels in predicting the outcome of in vitro fertilization treatment and that GnRHa in the long protocol do not seem to be superior to CC combined with hMG for the treatment of poor responders.     

The use of the GnRH analogue buserelin for IVF--does it improve fertility?

OBJECTIVE--To determine the effect of a short course of the GnRH analogue buserelin and human menopausal gonadotrophin (hMG), for ovarian stimulation in our IVF programme, on reproductive endocrinology and pregnancy rates compared with conventional clomiphene citrate and hMG treatment. DESIGN--Prospective randomized allocation to one of two ovulation stimulation regimens. SETTING--Fertility clinic. SUBJECTS--373 infertile couples with various factors associated with their subfertility. All the women were less than 46 years of age and had normal menstrual cycles. INTERVENTION--The first group (n = 151) was given clomiphene citrate (CC) from days 2-6 of the menstrual cycle and hMG from day 5 onwards (CC/hMG). The second group (n = 222) was given buserelin from days 1-3 and hMG from day 2 (buserelin/hMG). MAIN OUTCOME MEASURES--Concentration of plasma luteinizing hormone (LH), oestradiol (E2) and progesterone, number of ovulatory follicles induced and the occurrence of pregnancy. RESULTS--Plasma LH, E2 and progesterone concentrations were reduced in the late follicular phase after buserelin/hMG compared with CC/hMG. Buserelin/hMG promoted the development of more follicles than CC/hMG. The overall pregnancy rate after buserelin/hMG was not significantly different from that following CC/hMG treatment. CONCLUSION--The chance of pregnancy is not improved by the short-term use of buserelin with hMG, provided adequate follicular phase management is maintained.