Robert G. Brzyski

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.

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.

Recurrent failure of in vitro fertilization: role of the hemizona assay in the sequential diagnosis of specific sperm-oocyte defects.

The results of predictive fertilization bioassays (hemizona assay, hamster ova-human sperm penetration assay), in vitro fertilization treatment, fertile donor cross-match tests with either sperm or oocytes, and oocyte micromanipulation for assisted fertilization were used to establish a pathophysiologic diagnosis in cases of recurrent failed fertilization in vitro. Disorders of sperm function manifested at the level of zona binding, zona penetration, oolemma fusion, and pronuclear decondensation as well as oocyte anomalies were considered to represent the specific gamete defects that led to abnormal sperm-oocyte interactions (i.e., failed fertilization). Our findings show that the sequential application of bioassays can elucidate specific sperm or oocyte defects that characterize functional abnormalities among sperm populations.

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.

Equivalency of human menopausal gonadotropin and follicle-stimulating hormone stimulation after gonadotropin-releasing hormone agonist suppression*

This study compares the use of human menopausal gonadotropin (hMG) versus follicle-stimulating hormone (FSH), after gonadotropin-releasing hormone agonist (GnRH-a) suppression for in vitro fertilization. Thirty-seven patients were randomized to ovarian stimulation with either hMG or pure FSH. The GnRH-a leuprolide acetate was administered to all patients beginning in the midluteal phase of the prior cycle and continuing until the day of human chorionic gonadotropin (hCG) administration. There were no significant differences between hMG and FSH cycles with regard to the day of hCG administration, mean peak estradiol levels, number of ampules of medication used, and number of oocytes aspirated, embryos transferred, or pregnancies. We conclude that there is no significant difference between hMG and FSH stimulation when used in conjunction with GnRH-a.

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 preembryos 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 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.

Embryo transfer to the uterus or the fallopian tube after in vitro fertilization yields similar results

The outcome of ZIFT and IVF-ET was compared in consecutive nontubal factor patients in a prospective fashion. Groups did not differ in characteristics and were matched by the number of prezygotes/pre-embryos transferred. Overall, implantation, pregnancy, miscarriage, and ongoing PRs were not statistically different. These results suggest that ZIFT offers no significant advantage over IVF-ET for the treatment of nontubal infertility.

Increase in androgen:estrogen ratio specifically during low-dose follicle-stimulating hormone therapy for polycystic ovary syndrome

OBJECTIVES To compare changes in serum androgens in women with polycystic ovary syndrome (PCOS) during ovulation induction with low-dose versus conventional urofollitropin. DESIGN Prospective case-control study. SETTING Tertiary-care reproductive medicine center. SUBJECTS Thirty-three women with PCOS who failed to conceive with clomiphene citrate therapy. INTERVENTIONS Urofollitropin (low-dose, 75 IU; conventional dose, 150 IU) was administered IM daily. Therapy was monitored by serum E2 and vaginal sonography. Hormone determinations were performed by immunoassay. MAIN OUTCOME MEASURES Serum E2, androstenedione (A), T, and LH levels. RESULTS On the day of hCG administration, patients treated with low-dose therapy exhibited significantly higher ratios of A to E2 (3.5 +/- 0.5 versus 2.2 +/- 0.3 [mean +/- SEM]) and T to E2 (1.5 +/- 0.3 versus 1.0 +/- 0.1) compared with conventional urofollitropin therapy. The number of follicles > or = 16 mm in diameter was significantly lower with low-dose therapy (2.7 +/- 0.6 versus 5.4 +/- 0.4). CONCLUSIONS Although low-dose therapy was associated with a reduction in the number of recruited follicles, the increase in androgen to E2 associated with this therapy may adversely affect oocyte quality and may explain the relatively high miscarriage rate reported in PCOS patients with this therapy.

Effects of leuprolide acetate on follicular fluid hormone composition at oocyte retrieval for in vitro fertilization

The follicular fluid (FF) in 91 follicles from 17 women treated with leuprolide acetate (LA) before stimulation with gonadotropins for in vitro fertilization were analyzed for estradiol (E2), progesterone (P), androstenedione, prolactin, and human chorionic gonadotropin (hCG) and compared with the concentrations in 128 follicles from 31 women treated with gonadotropins alone. The FF E2 concentration in LA-treated patients was significantly lower than in non-LA patients for all oocyte maturational stages. Follicles containing metaphase II oocytes had significantly lower concentrations of P and hCG in LA-treated patients. These differences persisted when analysis was limited to follicles whose oocytes fertilized normally. These data indicate that in the presence of LA, normal oocyte maturation can occur despite lower intrafollicular concentrations of E2 and P.

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.