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


METHODS
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.


CONCLUSIONS
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.
Minaretzis
D
D
Department of Obstetrics and Gynecology and Reproductive Biology, Beth Israel Hospital, Boston MA 02215, USA.
Alper
M M
MM
Oskowitz
S P
SP
Lobel
S M
SM
Mortola
J F
JF
Pavlou
S N
SN
D000328:Adult; D001141:Aromatase / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D004958:Estradiol / Q000097:blood; D005260:Female; D005307:Fertilization in Vitro; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D005498:Follicular Phase; D015181:Gamete Intrafallopian Transfer; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D006107:Granulosa Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D016729:Leuprolide / Q000627:therapeutic use*; D008184:Luteal Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood / Q000494:pharmacology; D008597:Menstrual Cycle / Q000187:drug effects*; D009865:Oocytes / Q000166:cytology / Q000187:drug effects; D010062:Ovulation Induction; D011374:Progesterone / Q000096:biosynthesis*; D011446:Prospective Studies
C057805:LHRH, N-Ac-2-Nal(1)-4-Cl-Phe(2)-3-Pal(3)-Arg(5)-Glu(6)-AlaNH2(10)-; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D001141:Aromatase; D016729:Leuprolide