Microdose follicular phase gonadotropin-releasing hormone agonists (GnRH-a) compared with luteal phase GnRH-a for ovarian stimulation at in vitro fertilization

Objective: To compare an ovarian stimulation protocol using microdose follicular phase GnRH agonist (GnRH-a) and oral contraceptive (OC) pills to a luteal phase GnRH-a protocol.

Design: Retrospective analysis.

Setting: University affiliated IVF program.

Patient(s): One hundred seventy patients who underwent IVF and ET in 1996.

Intervention(s): Patients were assigned to either a midluteal start of leuprolide acetate (LA) 1 mg/d, reduced to 0.5 mg/d after addition of gonadotropins (LUT), or OC pills until cycle day 0 followed by 20 μg of LA every 12 hours on cycle day 3 with addition of gonadotropins on cycle day 5 (MICRO).

Main Outcome Measure(s): Number of FSH ampules, days of stimulation, peak E₂, and number of oocytes retrieved.

Result(s): There were no statistically significant differences in the main outcome measures between the two groups using an age-matched ANOVA. Clinical pregnancy rate per cycle start was not statistically different (LUT = 54%, and MICRO = 37%). The cancellation rate was significantly higher in the MICRO group (22.5% vs. 8.2%).

Conclusion(s): Given the higher cancellation rate in the microdose group, a randomized clinical trial is required to determine the possible benefit of a lower dose of GnRH-a in patients with normal ovarian function.     

The long protocol of administration of gonadotropin-releasing hormone agonist is superior to the short protocol for ovarian stimulation for in vitro fertilization.

OBJECTIVE: To investigate whether pituitary desensitization with the gonadotropin-releasing hormone agonist (GnRH-a), buserelin acetate, before the administration of human menopausal gonadotropin (hMG) for ovarian stimulation in in vitro fertilization (IVF) is superior to the simultaneous administration of both hormones at the beginning of the treatment cycle. DESIGN: Prospective randomized study. PATIENTS: Ninety-one patients having their first attempt at IVF. INTERVENTIONS: Patients in group 1 (long protocol) were administered subcutaneous (SC) buserelin acetate 200 micrograms/d from day 1 of the menstrual cycle, and hMG was started only after pituitary desensitization had been achieved at least 14 days later. Patients in group 2 (short protocol) were administered SC buserelin acetate 200 micrograms/d from day 2 and the same dose of hMG used in the long protocol from day 3 of the menstrual cycle. RESULTS: The median total amount of hMG required in both groups was comparable. There were significantly more follicles (P = 0.0001), oocytes (P = 0.0008), fertilized oocytes (P = 0.0001), and cleaved embryos (P = 0.0001), and a higher fertilization rate (P = 0.0047) in patients in group 1. The pregnancy rates per initiated cycle and per embryo transfer were 19.57% and 25.71% in group 1 compared with 8.89% and 16.67% in group 2. CONCLUSIONS: The long protocol is superior in terms of significantly greater follicular recruitment, oocyte recovery and fertilization rates, and significantly greater number of embryos available for transfer. In general, it is the preferred method when GnRH-a are used for ovarian stimulation in IVF.     

A prospective randomized comparison of routine buserelin acetate and a decreasing dosage of nafarelin acetate with a low-dose gonadotropin-releasing hormone agonist protocol for in vitro fertilization and intracytoplasmic sperm injection

OBJECTIVE: To compare the efficacy of a draw-back nafarelin acetate protocol with routine buserelin acetate administration for in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). DESIGN: Prospective clinical study. SETTING: Mie University School of Medicine, Tsu, Mie, Japan. PATIENT(S): One hundred sixty-nine women treated with IVF and 183 women treated with ICSI. INTERVENTION(S): Nafarelin acetate and buserelin acetate in ovarian hyperstimulation in IVF and ICSI were administered. MAIN OUTCOME MEASURE(S): The concentrations of estradiol (E(2)), FSH, LH, gonadotropin dosages; the number of oocytes retrieved, oocytes fertilized, and embryos; and pregnancy rates. RESULT(S): A prospective study was conducted with 44 cycles for 34 couples with nafarelin acetate (group 1) and 47 cycles for 40 couples with buserelin acetate (group 2) with a long IVF protocol; 68 cycles for 46 couples with nafarelin acetate (group 3) and 56 cycles for 39 couples with buserelin acetate (group 4) with a short IVF protocol; 39 cycles for 32 couples with nafarelin acetate (group 5) and 50 cycles for 30 couples with buserelin acetate (group 6) with a long ICSI protocol; and 87 cycles for 60 couples with nafarelin acetate (group 7) and 81 cycles for 61 couples with buserelin acetate (group 8) with a short ICSI protocol. Patients were randomized to receive either full-dose nafarelin acetate (200 microg b.i.d.) treatment for 7 days followed by half-dose nafarelin acetate (200 microg daily) or buserelin acetate (300 microg t.i.d.). There were no statistically significant differences in baseline concentrations of E(2) and FSH, concentrations of E(2), P4, FSH, LH on hCG administration, gonadotropin dosage, the number of oocytes retrieved and embryos transferred, or pregnancy rates between groups 1 and 2, groups 3 and 4, groups 5 and 6, and groups 7 and 8. CONCLUSION(S): Full-dose nafarelin acetate treatment for 7 days followed by half-dose nafarelin acetate ("draw-back" protocol) is an effective new protocol for IVF and ICSI.     

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.     

Comparison of leuprolide acetate and triptorelin in assisted reproductive technology cycles: a prospective,randomized study

OBJECTIVE: To compare the use of two depot GnRH-a, leuprolide and triptorelin, in long-suppression GnRH-a protocols. DESIGN: Prospective, randomized study. SETTING: An IVF unit of an academic medical center.Fifty-two women who underwent controlled ovarian hyperstimulation and IVF. INTERVENTION(S): Patients were prospectively randomized to receive 3.75 mg depot formulations of either leuprolide or triptorelin on days 21-23 of the menstrual cycle. Stimulation with gonadotropins was initiated after pituitary desensitization was achieved. MAIN OUTCOME MEASURE(S): The stimulation pattern and cycle outcomes were compared between the two groups. RESULT(S): Twenty-six patients were included in each group. No significant differences were observed in the patient age, estrogen, and P levels on day of hCG administration, gonadotropin dosage, number of oocytes retrieved, fertilization rate, percentage of high-quality embryos, and number of embryos transferred. However, significantly higher clinical implantation and pregnancy rates were found in the leuprolide group compared with the triptorelin group. CONCLUSION(S): A depot preparation of leuprolide is associated with higher implantation and pregnancy rates than a depot preparation of triptorelin when it is used in the midluteal phase as part of the long-suppression GnRH-a protocol in IVF.     

A controlled study of gonadotropin-releasing hormone agonist (buserelin acetate) for folliculogenesis in routine in vitro fertilization patients

STUDY OBJECTIVE: To determine if gonadotropin-releasing hormone agonist (GnRH-a) and gonadotropin therapy could improve folliculogenesis and pregnancy rates (PRs) in women with a previously satisfactory response to clomiphene citrate and human menopausal gonadotropin (hMG). DESIGN: Randomized prospective study. SETTING: Assisted reproduction clinic. PATIENTS: One hundred fifty-seven women were randomized to receive either hMG alone or the GnRH-a buserelin acetate 600 microgram/d or buserelin acetate 1,200 microgram/d plus hMG. RESULTS: Compared with hMG alone, pretreatment with buserelin acetate significantly increased the PR per cycle started by preventing a premature luteinizing hormone rise and thereby reducing the number of abandoned cycles. There was, however, no difference between the number of follicles aspirated, oocytes obtained, or fertilization rates between groups. Furthermore, agonist therapy significantly increased both the dose of hMG required and the duration of stimulation. CONCLUSION: The routine use of GnRH-a in in vitro fertilization programs must be questioned.     

Prognostic factors in controlled ovarian hyperstimulation

OBJECTIVE: To determine whether the number of retrieved oocytes and the required amount of gonadotropins per oocyte in IVF treatment can be predicted with use of the following independent predictive variables: age, parity, cause of infertility, body mass index, day 3-5 FSH, E2, inhibin B, ovarian volume, the number of follicles, and intraovarian and uterine artery vascular resistance measured by ultrasonography before ovarian hyperstimulation. DESIGN: A retrospective analysis. SETTING: University hospital infertility clinic. PATIENT(S): Seventy-four consecutive women attending the university hospital infertility clinic for IVF treatment. INTERVENTION(S): The investigated factors were measured on day 3-5 of the cycle, in which luteal phase suppression was begun before ovarian hyperstimulation preparatory to IVF. MAIN OUTCOME MEASURE(S): The amount of gonadotropins required per oocyte and the number of retrieved oocytes were correlated with the predictive factors in stepwise regression analysis. RESULT(S): The best predictive factors for the number of oocytes retrieved were FSH, inhibin B, and parity, explaining 25% of the ovarian response. Intraovarian vascular resistance, parity, FSH, and inhibin B best predicted the amount of gonadotropins needed, explaining 44% of the variation. CONCLUSION(S): FSH, inhibin B, and parity were the independent predictive factors for the number of retrieved oocytes. The same factors and intraovarian vascular resistance predicted the required amount of gonadotropins per oocyte. The main part of the ovarian response cannot be predicted using the factors investigated.     

Randomized trial of three luteinizing hormone-releasing hormone analogues used for ovarian stimulation in an in vitro fertilization program.

OBJECTIVE: To determine if biochemical differences in luteinizing hormone-releasing hormone analogues (LH-RH-a) have a clinical influence, we studied three of these molecules: buserelin acetate (group B), triptorelin (group T), and leuprorelin (group L). DESIGN: Clinical trial. SETTING: In Vitro Fertilization (IVF) Center. PATIENTS: Two hundred forty-six patients, undergoing their first IVF attempt, were randomly allocated to one group. The analogues were used in a long protocol for ovarian stimulation in an IVF program. RESULTS: After 15 days of LH-RH-a therapy, the follicle-stimulating hormone level was lower in group B (2.9 +/- 1, 4.3 +/- 1.7, 4.8 +/- 2.1 UI/L for B, T, and L groups, respectively; P less than 0.001), although no difference was found in LH and estradiol (E2) levels. After follicular growth stimulation by human menopausal gonadotropins (hMG), E2 level was significantly lower in B group (1,799 +/- 1,101, 2,440 +/- 1,298, 2,137 +/- 1,044 pg/mL for B, T, and L groups, respectively; P less than 0.01), as well as the E2 level per hMG ampule (67 +/- 51, 97 +/- 61, 82 +/- 49 for B, T, and L groups respectively; P less than 0.01). The pregnancy per stimulated cycle rate was not significantly different among the groups. CONCLUSIONS: These results suggest that LH-RH-a could act not only on the pituitary but also on the ovaries. Moreover, these data suggest that buserelin acetate could be preferentially used for high responders and triptorelin for poor responders.     

Chromosome studies in human unfertilized oocytes and uncleaved zygotes after treatment with gonadotropin-releasing hormone analogs

OBJECTIVE: To determine the frequency of the anomalies from the cytogenetic point of view in the oocytes remaining from our in vitro fertilization (IVF) program. Two gonadotropin-releasing hormone analogs (GnRH-a) were used (buserelin acetate and leuprolide acetate) in the superovulation treatment. DESIGN: A prospective study was planned in January 1989. Deadline for data and quantitative analysis was to be July 1990. SETTING: Hospital de Cruces, a public and tertiary institute. PATIENTS: One hundred thirty-nine IVF patients, yielding 433 oocytes. Selected on the basis of availability of oocytes and staff. RESULTS: Two hundred thirty-eight oocytes (71.25%) exhibited the normal number of metaphase II chromosomes; 64 (19.16%) exhibited aneuploidy; 13 (3.89%) were diploid, hyperdiploid, or hypodiploid; and 19 (5.68%) showed parthenogenetic activation. Of the 99 zygotes, 17 were polyploid and 48 showed prematurely condensed chromosomes, whereas in 31 cases the male and female pronuclei remained separate. CONCLUSIONS: It would not appear that the rate of chromosomal anomalies is affected after pituitary suppression with GnRH-a.     

Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist

OBJECTIVE: To use gonadotropin-releasing hormone agonist (GnRH-a) instead of human chorionic gonadotropin (hCG) to induce oocyte maturation for in vitro fertilization (IVF). DESIGN: Pituitary and ovarian responses to GnRH-a and the outcome of IVF were studied prospectively. Data from patients injected with hCG were analyzed retrospectively. SETTING: Program of IVF at the Rambam (Governmental) Hospital, Haifa, Israel. PATIENTS AND INTERVENTIONS: One or two doses of buserelin acetate 250 to 500 micrograms were administered to six patients with moderate response (Estradiol [E2], 1,494 +/- 422 [+/- SD] pg/mL) and 8 patients with exaggerated response (E2, 7,673 +/- 3,028 pg/mL) to gonadotropin stimulation. Progesterone (P) and E2 were administered for luteal support. MAIN OUTCOME MEASURES: Gonadotropin-releasing hormone agonist effectively triggered luteinizing hormone (LH)/follicle-stimulating hormone (FSH) surge. Mature oocytes were recovered in all patients. Luteal E2 and P were lower than in patients injected with hCG. No signs of ovarian hyperstimulation syndrome were observed. RESULTS: Serum LH and FSH rose over 4 and 12 hours, respectively, and were significantly (P less than 0.05) elevated for 24 hours. Of all mature oocytes, 67% fertilized and 82% cleaved. Four pregnancies were obtained. CONCLUSIONS: A bolus of GnRH-a is able to trigger an adequate midcycle LH/FSH surge, resulting in oocyte maturation and pregnancy. Our preliminary results also suggest that it allows a more accurate control of ovarian steroid levels during the luteal phase and may prevent the clinical manifestation of ovarian hyperstimulation syndrome.     

Gonadotropin-releasing hormone agonists induce meiotic maturation and degeneration of oocytes in the in vitro perfused rabbit ovary

The present study was undertaken to assess the effects of gonadotropin-releasing hormone agonists (GnRH-a, buserelin and leuprolide acetate [LA]) on ovulation, oocyte maturation and degeneration, and steroid and prostaglandin production in the perfused rabbit ovary preparation. Ovulation did not occur in any of ovaries treated with buserelin or LA (10(2) to 10(4) ng/mL) in the absence of gonadotropin. Gonadotropin-releasing hormone agonists were associated with the resumption of meiosis in follicular oocytes in a dose-related manner. Furthermore, the addition of GnRH-a to the perfusate significantly increased the percentage of follicular oocytes that showed evidence of degeneration compared with contralateral untreated or human chorionic gonadotropin-treated controls. Prostaglandin E2 and prostaglandin F2 alpha production by the perfused rabbit ovaries were stimulated significantly by GnRH-a treatment. Exposure to GnRH-a failed to increase either progesterone or estradiol production by the perfused rabbit ovaries. These data demonstrate that GnRH-a act directly in the rabbit ovary to trigger meiotic maturation in oocytes within the follicles, concomitantly increasing oocyte degeneration.     

Comparison of stimulation with clomiphene citrate in combination with recombinant follicle-stimulating hormone and recombinant luteinizing hormone to stimulation with a gonadotropin-releasing hormone agonist protocol: a prospective,randomized study

OBJECTIVE: To compare IVF-ET outcome with a new stimulation protocol using clomiphene citrate (CC) with recombinant FSH and LH to stimulation with the standard long GnRH-a protocol. DESIGN: Prospective randomized study. SETTING: Outpatient infertility clinic in Vienna, Austria. PATIENT(S): Two hundred ninety-four infertile women undergoing IVF-ET; 154 IVF cycles stimulated with CC + recombinant FSH + recombinant LH (group A) and 140 cycles with long GnRH-a suppression + recombinant FSH (group B). INTERVENTION(S): Controlled ovarian hyperstimulation, egg retrieval, and ET. MAIN OUTCOME MEASURE(S): Cycle parameters (number of oocytes, fertilization, number of embryos) and outcome (pregnancy rate, cancellation rate, ovarian hyperstimulation syndrome [OHSS]). RESULT(S): Pregnancy rate per ET was 42.9% (implantation rate, 21.3%) in group A and 36.6% (17.4%) in group B. Cancellation rates were similar. The OHSS occurred in four cases (3%) in group A and 12 cases (10%) in group B. CONCLUSION(S): Stimulation with CC + recombinant FSH + recombinant LH leads to comparable pregnancy rates vs. the long protocol. With this new stimulation, less gonadotropins are used and there is less need for monitoring (lower cost for patient and clinic). The risk of OHSS is reduced as well. Therefore, this protocol should be regarded as the first-line treatment.     

Impact of leuprolide acetate on the response to follicular stimulation for in vitro fertilization in patients with normal basal gonadotropin levels

Fifteen women with normal basal gonadotropin levels and adequate responses to conventional gonadotropin stimulation for in vitro fertilization (IVF) were pretreated with leuprolide acetate (LA) beginning in the midluteal phase prior to a repeat IVF attempt. A significantly longer duration of stimulation requiring a significantly higher total dosage of gonadotropins was observed in LA cycles. The number of preovulatory oocytes retrieved and preembryos transferred was significantly higher in LA cycles. Six of 15 women (40%) had cryopreservation of supernumerary preembryos in LA cycles, versus none in non-LA cycles; 22% of preovulatory oocytes aspirated in LA cycles were available for cryopreservation for future transfer. Five pregnancies occurred in the 15 LA cycles. IVF patients with normal basal gonadotropin levels and normal responses to conventional gonadotropin stimulation benefit from LA pretreatment.     

超短方案在卵巢低反应患者中的应用

目的:探讨体外受精-胚胎移植(in vitro fertilization-embryo transfer,IVF-ET)周期中,超短方案在卵巢低反应患者(poor ovarian responders,PORs)中的应用。方法:回顾性分析342例PORs的401个IVF周期,根据促排卵方案不同分为超短方案组(A组,254例,291个周期)和微刺激方案组(B组,88例,110个周期)。比较A、B组的一般资料、妊娠结局以及周期取消率等指标,分析A、B组周期取消原因。结果:临床妊娠率/移植周期、种植率和流产率组间均无统计学差异(P>0.05),但A组累积妊娠率显著高于B组(25.1%vs 14.5%,P<0.05),周期取消率显著低于B组(17.5%vs 44.5%,P<0.05)。周期取消原因分析表明,微刺激组因内膜因素取消移植的比例显著高于超短方案组(22.4%vs 7.8%,P<0.05)。结论:在PORs中,超短方案周期取消率低,患者心理压力小,整个疗程耗时短。因此超短方案也是PORs可以选择的、较理想的促排卵方案。     

Performance of cryopreserved pre-embryos obtained in in vitro fertilization cycles with or without a gonadotropin-releasing hormone agonist.

OBJECTIVE: To evaluate the viability and potential for pregnancy of cryopreserved/thawed pre-embryos obtained after ovarian stimulation using gonadotropin-releasing hormone agonist (GnRH-a) adjunct therapy. DESIGN: Retrospective clinical evaluation of all patients receiving a gonadotropin ovarian stimulation protocol (follicle-stimulating hormone/human menopausal gonadotropin [FSH/hMG]) with/without GnRH-a. SETTING: Academic tertiary clinical care unit. PATIENTS: Patients receiving leuprolide acetate (LA)/FSH/hMG (n = 136: LA in the luteal phase; long protocol) were compared with patients receiving FSH/hMG alone (n = 130) within the same time-frame in our program (April 1987 through October 1989). INTERVENTIONS: All patients had both a cycle in which pre-embryos were transferred fresh and a cycle of thaw of cryopreserved pre-embryos (frozen at the pronuclear stage in a slow freeze-thaw protocol using 1,2 propanediol) transferred in monitored natural cycles. MAIN OUTCOME MEASURES: Groups were similar in age, etiology of infertility, and cycle day 3 serum FSH levels; a significantly higher (P less than 0.001) number of preovulatory oocytes was recovered in the GnRH-a group. Both groups of patients were transferred an equal number of pre-embryos at the time of IVF. Cycles with frozen/thawed pre-embryos were evaluated based on the analysis of the three main variables that demonstrate cryopreservation efficiency: survival rate, implantation rate, and term pregnancy rate (PR). RESULTS: Non-GnRH-a group (113 transfers): pre-embryo survival, 71.5%; PR/transfer, 24.7%; implantation rate, 16.0%; GnRH-a group (125 transfers): pre-embryo survival 71.6%; PR/transfer, 32.8%; implantation rate, 12.0% (no significant differences). CONCLUSIONS: The use of GnRH-a produced pre-embryos of equal aptitude for development after cryopreservation at the pronuclear stage when compared with a similar gonadotropin stimulation treatment without GnRH-a.     

The gonadotropin-releasing hormone agonist stimulation test--a sensitive predictor of performance in the flare-up in vitro fertilization cycle

OBJECTIVE: To evaluate the initial versus early pattern of estradiol (E2) change after administration of a gonadotropin-releasing hormone agonist (GnRH-a), i.e., the GnRH-a stimulation test versus E2 pattern, respectively, as predictors of ovarian response and pregnancy in in vitro fertilization (IVF) patients stimulated with a flare-up protocol. DESIGN: Prospective study in a consecutive group of patients. SETTING: Tertiary care, institutional setting. PATIENTS: Two hundred twenty-eight patients entered and completed the study. The only patients excluded from study were those anticipated to have polycystic ovarian disease, those with a single ovary, or those with an ovarian cyst(s). INTERVENTIONS: Patients were stimulated with a GnRH-a flare-up protocol beginning on menstrual day 2. MAIN OUTCOME: Evaluation of the GnRH-a stimulation test and the E2 pattern as predictors of the number of mature oocytes retrieved and pregnancy. RESULTS: The GnRH-a stimulation test but not the E2 pattern was predictive of the number of mature oocytes retrieved (r = 0.53, P less than 1 X 10(-5) and pregnancy (chi 2 = 8.5, P = 0.04). The E2 pattern was predictive of the duration and number of ampules of gonadotropin required for stimulation. CONCLUSION: The GnRH-a stimulation test is a sensitive predictor of performance in the flare-up IVF cycle.     

The routine use of gonadotropin-releasing hormone agonists for all patients undergoing in vitro fertilization. Is there any medical advantage? A prospective randomized study.

OBJECTIVE: To determine if the routine use of gonadotropin-releasing hormone agonists (GnRH-a) for all patients undergoing in vitro fertilization (IVF) produces any significant medical advantage. DESIGN: Prospective randomized study. PATIENTS: Three hundred eight patients having their first ever IVF attempt. INTERVENTIONS: Patients were randomly divided into four groups and received either human menopausal gonadotropin (hMG) alone for ovarian simulation (group A, n = 81); clomiphene citrate and hMG (group B, n = 77); a 3-day ultrashort course of GnRH-a and hMG (group C, n = 74); or pituitary desensitization with GnRH-a followed by hMG (group D, n = 76). RESULTS: The indications for IVF and mean age of all four groups of patients were comparable. There was a significant difference in the number of embryos cleaved and transferred among the groups, but there were no significant differences in the cancellation rate, mean number of oocytes collected or fertilized, and number of cases of failed fertilization. There were also no significant differences in the pregnancy and live birth rates per cycle commenced or per embryo transfer. CONCLUSION: The routine use of GnRH-a for all patients undergoing IVF has practical but no significant medical advantages.     

The Effects of Gonadotropin-Releasing Hormone Agonist on Androstenedione Production and Follicular Development During Controlled Ovarian Hyperstimulation

Purpose: We performed a prospective randomized study to assess the effects of a GnRH agonist (GnRH-a) onfollicular development and steroidogenesis during controlled ovarian hyperstimulation (COH). Methods: Patients undergoing in vitro fertilization (IVF)for tubal infertility received human menopausal gonadotropin (hMG) stimulation with or without the GnRH-a, buserelin, beginning in the midluteal phase of the prior cycle. We analyzed serum hormone levels, follicular development, and outcome of IVF. Results: The mean number of retrieved oocytes was significantly greater, and the implantation rate per embryo was significantly higher, in the GnRH-a/hMG group (n = 101) than in the hMG-only group (n = 97). The concentration of androstenedione (A) and the A/estradiol ratio in the serum were significantly lower in the GnRH-a treatment group throughout the follicular phase. Conclusions: The concomitant use of GnRH-a during COH prevents atretic change of the follicles and enhances follicular development by reducing androgen accumulation, resulting in a higher developmental competence of the oocytes.     

Exogenous gonadotropin stimulation is associated with increases in serum androgen levels in in-vitro fertilization-embryo transfer cycles

Objective: To examine serum androgen profiles in women undergoing ovarian stimulation with exogenous gonadotropins in the setting of IVF-ET.

Design: Prospective study.

Setting: University hospital IVF-ET program.

Patient(s): Seventeen ovulatory women undergoing IVF-ET for endometriosis, male factor infertility, or tubal disease.

Intervention(s): A standard long protocol of GnRH agonist (GnRH-a) pretreatment (1 mg of leuprolide acetate SC for 10 days) was administered before ovulation induction with a urinary gonadotropin preparation.

Main Outcome Measure(s): After 10 days of GnRH-a treatment and on the day of hCG administration, serum concentrations of LH, T, androstenedione (A), sex hormone-binding globulin (SHBG), and DHEAS; the free androgen index (T/SHBG); and the number of follicles, oocytes, and embryos were assessed.

Result(s): Serum samples after 10 days of GnRH-a treatment showed incomplete LH suppression. While continuing the agonist during ovarian stimulation, LH values were suppressed further. However, serum T and A concentrations and the free androgen index showed a significant increase (samples drawn just before hCG administration). Serum T levels after 10 days of GnRH-a (before the administration of exogenous gonadotropins) were correlated negatively with the subsequent number of embryos.

Conclusion(s): Serum LH suppression with a conventional regimen of GnRH-a is incomplete in this heterogeneous group of ovulatory women. Exogenous gonadotropin stimulation results in a marked increase in ovarian androgen secretion.     

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.