Joseph F. Mortola

Gonadotropin-releasing hormone antagonist versus agonist administration in women undergoing controlled ovarian hyperstimulation: Cycle performance and in vitro steroidogenesis of granulosa-lutein cells

OBJECTIVES We sought to determine the effectiveness of a gonadotropin-releasing hormone antagonist compared with an agonist in suppressing a spontaneous luteinizing hormone surge in women undergoing controlled ovarian hyperstimulation for in vitro fertilization and gamete intrafallopian transfer and to examine whether in vivo administration of these analogs effects granulosa-lutein cells steroidogenesis in vitro. STUDY DESIGN This prospective case-control study included 30 healthy women undergoing ovarian hyperstimulation with human menopausal gonadotropins. Fifteen women received the Nal-Glu antagonist, 5 mg intramuscularly daily, when the lead follicle was > or = 15 mm or serum estradiol level was > or = 500 pg/ml. The control group included 15 women who underwent oocyte retrieval on the same day as the study subjects and were given the agonist leuprolide acetate, 250 micrograms subcutaneously daily, starting on cycle day 1. Granulosa-lutein cells were purified from follicular aspirates from six subjects and six controls and cultured in parallel, evaluating basal progesterone production, progesterone response to follicle-stimulating hormone or luteinizing hormone and aromatase activity. RESULTS No difference was demonstrated in the total amount of gonadotropins received by the two groups. Overall, the gonadotropin-releasing hormone antagonist was given for only 2.5 +/- 0.2 (mean +/- SEM) days before human chorionic gonadotropin administration. The antagonist group showed significantly lower levels of serum luteinizing hormone than did the agonist group, 1.0 +/- 0.2 versus 4.2 +/- 0.5 mIU/ml (p = 0.0001) on the day of human chorionic gonadotropin administration. Serum estradiol levels were significantly lower in the antagonist than the agonist group, 820 +/- 120 versus 1361 +/- 110 pg/ml (p = 0.003) on the day of human chorionic gonadotropin administration. There was no difference in the number of retrieved oocytes, but the antagonist group had a higher proportion of mature oocytes, 82% +/- 4% versus 62.4% (p = 0.02), and a higher proportion of embryos of good quality, 69.8% +/- 9.8% versus 44.3% +/- 7.2% (p = 0.03) in the agonist group. Granulosa-lutein cells from antagonist-treated women showed significantly lower aromatase activity the first 6 hours after retrieval, 17.6 +/- 1.6 versus 31.3 +/- 7.4 ng/ml per 6 hours estradiol (p = 0.03), whereas basal and gonadotropin-stimulated with progesterone responses were similar. CONCLUSION Gonadotropin-releasing hormone antagonist administration during the late follicular phase resulted in lower serum luteinizing hormone and estradiol levels and more mature oocytes and embryos of better quality compared with gonadotropin-releasing hormone agonist administration. These results suggest that gonadotropin-releasing hormone antagonist administration in ovarian hyperstimulation has practical advantages over the agonist regimen. Gonadotropin-releasing hormone analogs may have direct action on ovarian function with differential effects on granulosa-lutein cell aromatase activity. This could explain the lower serum estradiol levels routinely observed in women given gonadotropin-releasing hormone antagonist.

Multivariate Analysis of Factors Predictive of Successful Live Births in In Vitro Fertilization (IVF) Suggests Strategies to Improve IVF Outcome

Purpose:Our purpose was (1) to identify characteristics correlated with pregnancy outcome, (2) to use these characteristics to predict in vitro fertilization (IVF) outcome, and (3) to develop strategies that might improve IVF success.Methods:Maternal age, cause for IVF, donor insemination, rank of attempt, serum estradiol and luteinizing hormone levels on the day of human chorionic gonadotropin administration, flexible vs rigid catheter, number of embryos transferred of each morphologic type, and cell number were analyzed by logistic regression.Results:Variables positively correlated with success are as follows: (1) for pregnancy, endometriosis and 2-, 3-, and 4-cell good and 4-cell excellent embryos: (2) for live births, 2-, 3-, and 4-cell good and 4-cell excellent embryos and donor insemination; and (3) for multiple births, 2- and 4-cell good and 4-cell excellent embryos. Maternal age was negatively correlated with live births.Conclusions:Embryos derived from IVF have different potentials for implantation, live births, and multiple births. Transferring one additional good-quality embryo for each 5 years of incremental increase in maternal age is predicated to improve live birth rates without increasing multiple births.

Success rates with gamete intrafallopian transfer and in vitro fertilization in women of advanced maternal age

OBJECTIVE To evaluate the effect of maternal age on outcomes for IVF and GIFT in women 40 to 45 years of age. DESIGN Retrospective. SETTING Boston IVF, a free-standing university-affiliated IVF and GIFT unit. PATIENTS A total of 2,931 cycles of IVF and 1,826 cycles of GIFT were analyzed in women undergoing assisted reproductive technologies (IVF or GIFT) using autologous eggs. INTERVENTIONS Medical records of patient outcomes were reviewed. RESULTS For patients undergoing IVF, the cancellation rate for initiated cycles showed significant differences in women aged 25 to 39 (38.3%), women aged 40 to 43 (49.5%), and women aged 44 to 45 years (69.5%). A significantly lower delivery rate per stimulation and delivery rate per retrieval was found in women aged 40 to 43 years when compared with women aged 25 to 39 years. No deliveries occurred in 59 cycles in women aged 44 to 45 years, thereby representing a significant difference when compared with both women aged 25 to 39 years and women aged 40 to 43 years. For patients undergoing GIFT, the cancellation rate for initiated cycles was significantly higher in women aged 40 to 43 (25.0%) and 44 to 45 years (31.0%) when compared with women aged 25 to 39 years (15.1%). A significantly lower delivery rate per stimulation and delivery rate per retrieval was found in women aged 40 to 43 and 44 to 45 years when compared with women aged 25 to 39 years. CONCLUSIONS Success rates for IVF and GIFT decline significantly in women > 40 years old. Women aged > or = 44 years are unlikely to benefit from the use of IVF and GIFT.

Relationship Between Urinary Estrone Conjugates as Measured by Enzyme Immunoassay and Serum Estradiol in Women Receiving Gonadotropins for in Vitro Fertilization

ObjectiveOur purpose was to determine whether urinary estrone conjugates (E1C) as measured by enzyme immunoassay correlate with serum estradiol (E2) in women undergoing controlled ovarian hyperstimulation with human menopausal gonadotropins.DesignThis was a prospective, clinical study.SettingThe study took place in an outpatient, university-affiliated in vitro fertilization (IVF) unit.InterventionsFirst morning urine samples were analyzed for E1C using a competitive solid-phase microtiter enzyme immunoassay and the value was corrected for urinary creatinine (E1C/Cr). The value was compared to morning serum E2 as determined by radioimmunoassay.ResultsMean E2 and E1C/Cr levels demonstrated a similar pattern on the days before hCG administration. The correlation between E1C and E2 was 0.85 (P<0.0001). Furthermore, the correlation between the number of follicles greater than 12 mm was as high for E1C/Cr (ρ =0.71, P<0.001) as it was for E2 (ρ = 0.74, P<0.0001).ConclusionsUrinary E1C/Cr levels in women receiving hMG correlate with serum E2. Further studies are necessary to determine whether E1C is clinically useful to predict ovarian hyperstimulation syndrome.