Clinical outcome of using ganirelix acetate versus a 4-day follicular phase leuprolide acetate protocol in unselected women undergoing in vitro fertilization

OBJECTIVE: To compare the clinical outcome of controlled ovarian hyperstimulation (COH) in unselected patients undergoing IVF using multidose ganirelix acetate versus 4 days of administration of leuprolide acetate. DESIGN: Retrospective cohort study. SETTING: A fertility and IVF center. PATIENT(S): Two hundred forty-seven women who underwent COH-IVF between April 1, 1999, and January 30, 2001. INTERVENTION(S): Pituitary suppression according to a 4-day follicular phase leuprolide acetate protocol (236 women) or a multidose ganirelix acetate regimen (133 women). MAIN OUTCOME MEASURE(S): Amount of gonadotropin used, days of stimulation, cancellation rate, number of oocytes retrieved, implantation rate, and clinical pregnancy rate. RESULT(S): Compared with leuprolide acetate recipients, ganirelix recipients required significantly less gonadotropin and the mean day of hCG administration was 4 days earlier. Among women younger than 35 years of age, the implantation rate (15% vs. 6%) and the clinical pregnancy rate per initiated and transferred cycle (27% vs. 12% and 32% vs. 15%, respectively) were significantly higher in the ganirelix group than the leuprolide acetate group. CONCLUSION(S): Compared with a 4-day leuprolide acetate protocol, COH-IVF using a multidose ganirelix acetate protocol reduces treatment duration and amount of gonadotropin used. In younger women, the latter protocol is associated with significantly better pregnancy and implantation rates.     

Exogenous gonadotropin requirements are increased in leuprolide suppressed women undergoing ovarian stimulation

We used a subcutaneously administered GnRHa for 21 to 26 days prior to menotropin stimulation, to suppress endogenous LH surges in four patients participating in IVF. GnRHa-pretreated cycles were compared with previous menotropin treatment cycles. Endogenous LH surges were successfully suppressed in all patients. Peak E2 levels and ultrasonographic parameters of follicular development were comparable in the two treatment groups. Exogenous gonadotropin requirements were increased 2- to 4-fold in GnRHa pretreated cycles (P less than 0.05). Ovum recovery rates were not improved by adjuvant LA. These studies indicate that there was an increased ovarian requirement for exogenous gonadotropins as a result of GnRHa therapy. It has to be considered that this may be a direct effect of GnRHa upon the ovary. Alternatively, the absence of endogenous pituitary support in GnRHa-treated patients may account for the increased gonadotropin requirement. Finally, it is possible that this effect is indigenous to this select patient population of poor responders to menotropin stimulation, or to a specific effect of subcutaneously (as opposed to intranasally) administered GnRHa on the ovary. Further studies are needed to clarify the extent to which any or all of these postulated mechanisms may be influencing ovarian response to exogenous gonadotropins after subcutaneous GnRHa pretreatment.     

Ovarian hyperstimulation in polycystic ovary syndrome during therapy with leuprolide acetate

Continuous exposure to GnRH eliminates the pituitary as a source of gonadotropins and may have direct suppressive effects on the ovary. A woman with PCO syndrome received leuprolide acetate (1 mg/d SC) for 4 weeks before and simultaneously with hMG stimulation. Human chorionic gonadotropin (5,000 IU) was administered IM on the 8th day of hMG therapy. There were 10 follicles greater than 15 mm and a polycystic appearance to the ovaries with 25 follicles measuring less than 10 mm. The serum E2 concentration was 2,280 pg/mL. She developed severe ovarian hyperstimulation and required hospitalization for 12 days for fluid management. A viable intrauterine pregnancy was present. Four weeks of pretreatment with leuprolide did not prevent hyperstimulation in the presence of an intrauterine pregnancy.     

Value of suppression with a gonadotropin-releasing hormone agonist prior to gonadotropin stimulation for in vitro fertilization

This study examined the use of gonadotropin-releasing hormone agonist (GnRHa) suppression before gonadotropin stimulation in 26 patients with failed prior in vitro fertilization (IVF) attempts and variable basal serum gonadotropin levels. Leuprolide, 1 mg subcutaneously per day, was administered from the midluteal phase of the cycle before IVF treatment. Concomitantly, stimulation was initiated on cycle day 3 with human menopausal gonadotropin (hMG) and follicle stimulating hormone (FSH). Based on their prior IVF attempts and serum gonadotropin levels on cycle day 3, 9 patients were high responders with elevated mean basal luteinizing hormone (LH)/FSH, 8 were low responders with elevated mean basal FSH/LH, 7 were intermediate responders with normal mean basal FSH/LH and a history of premature LH surge, and 2 had elevated (perimenopausal) mean FSH and LH. Leuprolide was discontinued on the day of human chorionic gonadotropin (hCG) administration. Prior IVF attempts in the same patients with the same protocol, but without GnRHa suppression, were used as controls. The mean number of ampules of hMG and FSH was significantly higher in leuprolide cycles than in controls. The mean day of hCG administration was also higher for leuprolide cycles than for controls. The mean LH and progesterone levels on the day of hCG were significantly lower in leuprolide cycles. The mean number of preovulatory oocytes aspirated and transferred was higher in leuprolide cycles. Cancellation and pregnancy rates were improved in leuprolide cycles. It is concluded that prior GnRHa suppression is beneficial for follicular recruitment for IVF. More patients with variable basal serum gonadotropin levels need to be studied before definite recommendations are made.     

Comparison of Clinical Outcome and Costs with CC + Gonadotropins and GnRHa + Gonadotropins During IVF/ICSI Cycles

OBJECTIVE: To compare clinical outcome and costs of CC + gonadotropins with GnRHa + gonadotropins during IVF/ICSI cycles. MATERIALS AND METHODS: Clinical outcome and expenses of 382 CC + gonadotropin and 964 GnRHa + gonadotropin cycles were compared. Medication costs were calculated on the basis of the mean number of ampoules and the proportion of various gonadotropins. Costs per clinical pregnancy were calculated on the basis of expenses and clinical pregnancy rates. RESULTS: Women in the CC + gonadotropin group were younger, and had fewer follicles, oocytes, embryos, and embryos transferred. Clinical pregnancy rates were higher in the GnRHa group (35.9 % vs 26.2%, p < 0.001). More ampoules of gonadotropins were used in the GnRHa group (24.0 +/- 0.3 vs 20.0 +/- 0.5, p < 0.001). Medication costs per cycle were higher in the GnRHa group (US dollars 357 vs 248). Expenses per pregnancy however were lower in the GnRHa group (USdollars 4197 vs 5335 with IVF; USdollars 5590 vs 7244 with ICSI). When different age subgroups with similar baseline characteristics and stimulation parameters were compared, pregnancy rates were significantly higher in the GnRHa groups. Medication cost per cycle was higher in the GnRHa subgroups, and the expense per pregnancy was lower with GnRHa protocol. CONCLUSIONS: Cost per cycle is higher with GnRHa + gonadotropin. However, because of the better performance of the GnRHa + gonadotropin stimulation, the cumulative costs are reduced by the time a clinical pregnancy is achieved.     

Follicular atresia associated with concurrent initiation of gonadotropin-releasing hormone agonist and follicle-stimulating hormone for oocyte recruitment

The ability of gonadotropin-releasing hormone agonist (GnRHa) to cause an initial stimulation of serum gonadotropins was used for follicular recruitment for in vitro fertilization (IVF) in 12 patients with a history of low estradiol (E2) response to conventional gonadotropin stimulation. Stimulation was initiated on cycle day 3 with concurrent administration of leuprolide (1 mg/day subcutaneously) and follicle stimulating hormone (FSH, 4 ampules/day intramuscularly). An 8-fold increase in basal serum luteinizing hormone (LH) and a 4-fold increase in basal serum FSH was seen on cycle day 4. Serum progesterone levels rose significantly by day 6. When compared to prior IVF attempts in these patients, the mean day of human chorionic gonadotropin administration and corresponding E2 levels were not significantly different. More atretic oocytes and fewer preovulatory oocytes were retrieved using GnRHa, and no increase was seen in total oocytes retrieved. One patient was canceled for poor E2 response, and one patient conceived, with a current viable pregnancy. It is concluded that concurrent initiation of leuprolide and FSH stimulation on cycle day 3 in patients with prior low response does not improve oocyte recruitment, and the high LH environment generated from initial stimulation of the agonist may be detrimental to normal oocyte development.     

Effect of antagonists vs agonists on in vitro fertilization outcome

PURPOSE: To compare outcome following in vitro fertilization-embryo transfer (IVF-ET) using controlled ovarian hyperstimulation (COH) regimens using either the gonadotropin-releasing hormone (GnRH) agonist leuprolide acetate vs the GnRH antagonist ganirelix. METHODS: Women needing IVF for conception were randomly assigned to 300 IU of gonadotropins with ganirelix used in the follicular phase when a follicle with a 14 mm average diameter was attained vs a regimen using leuprolide acetate from the mid-luteal phase of the previous cycle. RESULTS: There were no differences found in clinical, ongoing, delivered pregnancy rates or implantation rates between groups. CONCLUSIONS: The use of GnRH antagonists do not seem to reduce IVF outcome compared to using GnRH agonists in COH regimens.     

Improved pregnancy outcome with the addition of leuprolide acetate to gonadotropins for in vitro fertilization

In vitro fertilization treatment outcomes were compared prospectively in unselected patients with and without the addition of leuprolide acetate to gonadotropins for ovarian hyperstimulation. While the leuprolide patients required greater quantities of exogenous gonadotropins to achieve ovarian stimulation, significant improvements in the fertilization, implantation, and spontaneous abortion rates were observed compared with patients not receiving leuprolide. The ongoing pregnancy ("take home baby") rates per aspiration with and without leuprolide were 29% and 12%, respectively. Furthermore, the multiple pregnancy rate was markedly increased in the leuprolide group (44% versus 8%), suggesting that the improved pregnancy outcome with pituitary suppression was due primarily to higher oocyte and embryo quality.     

Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation

OBJECTIVE: To assess the efficacy, safety, and local tolerance of ganirelix acetate for the inhibition of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation (COH). DESIGN: Phase III, multicenter, open-label randomized trial. SETTING: In vitro fertilization (IVF) centers in North America. PATIENT(S): Healthy female partners (n = 313) in subfertile couples for whom COH and IVF or intracytoplasmic sperm injection were indicated. INTERVENTION(S): Patients were randomized to receive one COH cycle with ganirelix or the reference treatment, a long protocol of leuprolide acetate in conjunction with follitropin-beta for injection. OUTCOME MEASURE(S): Number of oocytes retrieved, pregnancy rates, endocrine variables, and safety variables. RESULT(S): The mean number of oocytes retrieved per attempt was 11.6 in the ganirelix group and 14.1 in the leuprolide group. Fertilization rates were 62.4% and 61.9% in the ganirelix and leuprolide groups, respectively, and implantation rates were 21.1% and 26.1%. Clinical and ongoing pregnancy rates per attempt were 35.4% and 30.8% in the ganirelix group and 38.4% and 36.4% in the leuprolide acetate group. Fewer moderate and severe injection site reactions were reported with ganirelix (11.9% and 0.6%) than with leuprolide (24.4% and 1.1%). CONCLUSION(S): Ganirelix is effective, safe, and well tolerated. Compared with leuprolide acetate, ganirelix therapy has a shorter duration and fewer injections but produces a similar pregnancy rate.     

控制性超促排卵过程中血清LH低于正常时添加rLH或hMG的效果比较

目的:比较控制性超促排卵(COH)过程中血清促黄体生成素(LH)低于正常时添加基因重组LH(rLH)或人绝经期尿促性腺激素(hMG)的效果。方法:选取因输卵管因素不孕行常规IVF-ET患者85例,全部采用长方案超促排卵,均给予基因重组促卵泡激素(rFSH)进行超促排卵,超促排卵第6日时如血清LH≥1.2 mIU/ml,继续用rFSH,作为对照组(rFSH组,n=37);如血清LH<1.2 mIU/ml,则随机纳入到hMG组(rFSH+hMG,n=30)或rLH组(rFSH+rLH,n=18)。结果:3组间在促性腺激素(Gn)用量、COH天数、获卵数、双原核率、优质胚胎率、临床妊娠率方面均无统计学差异。hMG组的rFSH用量显著低于rLH组(P<0.01)。结论:在黄体期降调节长方案超促排卵第6日,如血清LH<1.2 mIU/ml时,添加hMG或rLH,可获得与对照组(rFSH组)相似的临床结果。与添加rLH组相比,添加hMG组降低了rFSH用量,减少了患者的费用。     

Cessation of Low-Dose Gonadotropin Releasing Hormone Agonist Therapy Followed by High-Dose Gonadotropin Stimulation Yields a Favorable Ovarian Response in Poor Responders

Purpose: This study is a prospective nonrandomized study to determine the effect of a new protocol of controlled ovarian hyperstimulation (COH) using low doses and a half-period of gonadotropin releasing hormone agonist (GnRHa) followed by high doses of gonadotropin in patients who were supposed to be poor responders to standard long protocols of GnRHa administration. Methods: From Dec 1996 to Nov 1998, 50 patients who were classified as poor responders were scheduled for 52 cycles of a modified controlled ovarian hyperstimulation protocol. They were categorized into 3 groups: a group of poor responders to COH in the previous IVF or IUI cycles, a group with elevated Day 3 FSH levels, and a group over the age of 40 years. All patients received GnRH agonist from the midluteal phase of the previous cycle to the onset of menstruation in the next cycle. Then high doses of gonadotropins (HMG/FSH) were given. The patients then had standard courses of in vitro fertilization and embryo transfer (IVF-ET) or transfallopian embryo transfer (TET). Results: Six of the 52 cycles of the modified protocols were cancelled because of poor ovarian response. One premature ovulation was noted before ovum retrieval was performed. In the other 45 cycles, an average of 6.3 mature oocytes were retrieved. The total pregnancy rate and implantation rate were 20.5 and 11.5%, respectively. Conclusions: The low dose and half duration of GnRHa therapy lessened the suppression of the response of the ovaries to COH compared with the regular long protocol of GnRHa down regulation therapy. This resulted in a low cancellation rate (11.8%), a favorable embryo implantation rate (11.5%), and an acceptable clinical pregnancy rate (20.5%).     

Follicular phase gonadotropin-releasing hormone agonist and human gonadotropins: a better alternative for ovulation induction in in vitro fertilization

Leuprolide acetate was used in 189 in vitro fertilization (IVF) cycles. Patients were allocated prospectively into two groups: In group A (96 cycles), leuprolide acetate was started on the 2nd menstrual cycle day of the actual IVF attempt. In group B (93 cycles), leuprolide acetate was started on the 3rd luteal phase day of the preceding IVF cycle. Ovulation was induced with a combination of pure follicle-stimulating hormone (FSH) and human menopausal gonadotropins (hMG), starting on or before the 5th cycle day, respectively. Leuprolide acetate and gonadotropins were continued until the day of human chorionic gonadotropin (hCG) administration. Follicular aspiration was carried out either by laparoscopy or by transvaginal ultrasound guidance. Group A required a lower number of FSH and hMG ampules than group B; nevertheless, there was no difference in the number of follicles, percentage of preovulatory oocytes or fertilization rate between the groups. The number of embryos transferred was 3.3 and 3.4, respectively. A significantly higher pregnancy rate was observed in group A (40.6% versus 27.7%) and a lower miscarriage rate (22.8% versus 36%) than in group B. In short, this study suggests that there is no need to administer leuprolide acetate routinely during the luteal phase of the preceding IVF cycle.     

Effect of microsurgical resection of the ovary on fertility in patients with polycystic ovary resistant to clomiphene citrate]

Thirteen patients with clomiphene citrate resistant polycystic ovary syndrome (PCO-CR) were documented by clinical and endocrine profile. Exogenous gonadotropins (HMG, hFSH, hCG), or gonadotrophin releasing hormone agonist (GnRHa) plus gonadotropins represent a new approach to induce ovulation in these (PCO-CR) patients. 92% of these patients ovulated with exogenous gonadotropin, nevertheless the pregnancy rate was only 53%. Five out seven PCO-RC patients did not achieve pregnancy with exogenous gonadotrophins, but they did after ovarian wedge resection. It is interesting to note that four of these patients achieved their second and third pregnancy without any therapy. The authors conclude that the ovarian wedge resection may had to improve in the quality of ovulation in this very selective group of infertile patients.     

Comparison of a single half-dose, long-acting form of gonadotropin-releasing hormone analog (GnRH-a) and a short-acting form of GnRH-a for pituitary suppression in a controlled ovarian hyperstimulation program

OBJECTIVE: To compare the effect of a single low-dose leuprolide acetate depot (LA depot) and leuprolide acetate (LA) on pituitary down-regulation in women undergoing controlled ovarian hyperstimulation (COH). DESIGN: Retrospective study.Setting: An IVF unit of an academic medical center. PATIENT(s): Women who underwent COH and IVF-ET. INTERVENTION(s): Pituitary down-regulation with half-dose LA depot (1.88 mg sc, group 1) or LA (0.5 mg/d sc, group 2) was started on menstrual days 21-23. MAIN OUTCOME MEASURE(s): The concentrations of estradiol (E(2)), FSH, LH, gonadotropin dosages, the numbers of oocytes retrieved, oocytes fertilized and embryos transferred, and pregnancy rates of the two groups were compared. RESULT(s): A total of 289 patients in group 1 and 158 in group 2 were included. There were no statistically significant differences between the two groups in baseline concentrations of E(2) and FSH, concentrations of E(2), FSH, and LH during hCG administration, gonadotropin dosage, the number of oocytes retrieved, the number of oocytes fertilized and embryos transferred, and pregnancy rates. CONCLUSION(s): Single half-dose LA depot offers a useful alternative for pituitary suppression in ovarian stimulation for IVF.     

Progesterone levels on the day of human chorionic gonadotropin administration in cycles with gonadotropin-releasing hormone agonist suppression are not predictive of pregnancy outcome

In in vitro fertilization (IVF) cycles using gonadotropin-releasing hormone agonist (GnRH-a) suppression, we investigated whether an elevated progesterone (P) level on the day of human chorionic gonadotropin (hCG) administration indicates premature luteinization and is associated with a lower pregnancy rate. We retrospectively studied 101 patients treated with the GnRH-a leuprolide acetate, begun in the luteal phase of the prior menstrual cycle and continued until the day of hCG administration. On the day of hCG, 72 patients had P less than 0.9 ng/mL and 29 had less than or equal to 0.9 ng/mL. Patients in the high P group had a significantly greater estradiol level on the day of hCG. No significant difference in clinical pregnancy rates or ongoing pregnancy rates occurred between the low P and high P groups. We conclude that in IVF cycles pretreated with GnRH-a, P levels on the day of hCG are not predictive of conceiving in that cycle.     

Leuprolide acetate: serum and follicular fluid concentrations and effects on human fertilization, embryo growth, and granulosa-lutein cell progesterone accumulation in vitro

Data from various animal models have demonstrated significant extrapituitary effects of gonadotropin-releasing hormone agonists. The purpose of this study was to determine the effects of therapeutic concentrations of leuprolide acetate on human granulosa-lutein cell steroidogenesis, fertilization, and embryo growth rates in vitro. During leuprolide administration, mean serum concentrations of leuprolide were less than 50 ng/ml and were undetectable 48 hours after cessation of administration. There was no effect of leuprolide on progesterone (P) secretion by granulosa-lutein cells cultured in the presence or absence of human chorionic gonadotropin. The effect of leuprolide on embryo growth rates was evaluated with the mouse two-cell embryo culture model and a retrospective review of early embryo growth rates in humans receiving adjunctive leuprolide therapy. There was no measurable effect of leuprolide on early embryo growth in either species. These data indicate that (1) serum and follicular and peritoneal fluid concentrations are undetectable 2 days after discontinuation of leuprolide; (2) there is no measurable effect of leuprolide on human or murine embryo growth rates up to the 8 cell stage in vitro; and (3) there is no measurable effect of leuprolide on granulosa-lutein cell P accumulation.     

Progesterone response to exogenous gonadotropins after suppression with leuprolide acetate in gamete intrafallopian transfer

Fifty-three cycle of ovarian stimulation with human menopausal gonadotropins after suppression of endogenous gonadotropin release with leuprolide acetate were completed for the purpose of performing gamete intrafallopian transfer. Thirty-seven biochemical pregnancies resulted, with 29 progressing to clinical status, for rates of 69.8% and 54.7%, respectively, per cycle. In comparing characteristics of the follicular recruitment phases of failed cycles to those of cycles resulting in pregnancies, no differences were observed in serum estradiol concentrations or follicular development. However, pregnancy rates were highly associated with peak concentrations of progesterone prior to the administration of human chorionic gonadotropin. Three levels of progesterone range were found on the basis of outcome: 6 high-progesterone cycles produced no pregnancies (0%), 32 mid-range progesterone cycles produced 31 pregnancies (97%), and 15 low-progesterone cycles produced six pregnancies (40%). The pregnancy rate in the last group improved when the luteal support was doubled.     

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.     

Midcycle administration of single-dose GnRHa for luteal phase failure in women with ovarian hyperstimulation. A report of five cases

BACKGROUND: Exogenous administration of gonadotropin-releasing hormone agonist (GnRHa) induces an endogenous midcycle gonadotropin surge. However, its use to induce ovulation and maintain luteal function in non-in vitro fertilization patients who receive ovarian stimulation is unknown. CASES: Five infertile women who underwent controlled ovarian hyperstimulation with human menotropin developed multiple ovarian follicles. In an attempt to circumvent the potential ovarian hyperstimulation syndrome, 1 mg of leuprolide acetate was administered subcutaneously to three patients in an attempt to induce the endogenous luteinizing hormone surge. All three patients began menstruation six to seven days after GnRHa administration with serum progesterone levels between 0.2 and 0.5 ng/mL. Similar ovarian stimulation cycles with ovulation induced by human chorionic gonadotropin in these individuals revealed a normal luteal phase length and midluteal progesterone levels. When double doses of leuprolide acetate were used on two patients, normal luteal length and midluteal serum progesterone levels occurred. CONCLUSION: A single bolus of GnRHa during the late follicular phase may be inadequate to initiate normal luteal function in cycles with ovarian hyperstimulation.     

GnRHa for adhesion formation after uterine serosal injury in an euestrogenic milieu

OBJECTIVE: To assess whether the adhesion-preventing effect of gonadotropin-releasing hormone agonist (GnRHa) is through hypoestrogenism. STUDY DESIGN: Four groups of previously ovariectomized rats received various combinations of depot leuprolide acetate injection (3.75 mg/kg/mo) subcutaneously, conjugated equine estrogens (50 micrograms/kg/d) orally and phosphate-buffered saline injection subcutaneously, yielding group 1, saline only; group 2, saline and conjugated equine estrogens; group 3, depot leuprolide acetate only; and group 4, depot leuprolide acetate and conjugated equine estrogens. Surgical adhesions were induced by monopolar cautery on the right uterine horn through laparotomy and were then scored on day 21 after surgery. RESULTS: Adhesion scores for rats that received conjugated equine estrogens and saline were significantly higher than scores of those given conjugated equine estrogens and depot leuprolide acetate, depot leuprolide acetate only and saline only (P = .019, .026 and .027, respectively). However, there was no significant difference in the adhesion scores for these three groups. CONCLUSION: Hypoestrogenism results in the development of fewer peritoneal adhesions postoperatively. Our findings also indicated that other mechanisms, in addition to those inducing hypoestrogenism, are at work in the adhesion-preventing effects of GnRHa therapy.