Agonist vs Antagonist Dr. Milton Leong

Gonadotrophin releasing hormone analogs GnRH analogs: GnRH-like molecules 2 types of GnRHa: agonists and antagonists Agonists initially enhance gonadotrophin released from the pituitary; but with continuing administration, cause down-regulation of the pituitary and reduced LH & FSH secretion Antagonists bind onto GnRH receptors and completely suppress the pituitary hormone secretion within a few hours Effects completely reversible after withdrawal

Agonists GnRH agonists are used in common treatment protocols: Long protocol – aims at complete pituitary suppression Short & ultra-short protocols – utilize the “flare-up” effect Usage in ART treatment is well established Combining the use of agonists and gonadotropins in IVF cycles give high pregnancy rates after IVF and ET

Antagonists - 1 GnRH antagonists can be administered as single dose or multi dose in either a fixed or a flexible protocol (Olivennes F et al, 2003; Mansour RT et al, 2003; Diedrich K et al, 2001) Usage in ART treatment is relatively new Advantages (Shapiro DB and Mitchell-Leef D, 2003): shorter duration of injectable drug treatment decreased gonadotropin requirement per cycle improved patient convenience lower overall treatment cost

Antagonists - 2 Bosch E et al (Fertil & Steril 2003; 80:1444-9) Prospective observational study to determine the prevalence and the effect of premature luteinization in GnRH antagonist IVF-ET cycles Antagonist was administered from stimulation day 6; serum P, E2, and LH were determined on the day of hCG administration Premature luteinization is frequent during antagonist IVF-ET cycles and is associated with lower pregnancy and implantation rates Progesterone elevations are not related to serum LH levels

Antagonists - 3 Fanchin R et al (Fertil & Steril 2004; 81:1554-9) Prospective longitudinal study to investigate whether premenstrual administration of antagonist coordinates early antral follicle sizes during the subsequent follicular phase On cycle day 2 (control/day 2), early antral follicles were measured by ultrasound, serum FSH and ovarian hormones were also determined; on day 25, a single 3mg cetrorelix was administered. On the subsequent day 2 (antagonist/day 2), participants were re-evaluated as on control/day 2 Follicular diameters and follicle-to-follicle size disparities were decreased FSH, E2, and inhibin B were lower on antagonist/day 2 than on control/day 2

Antagonists - 4 Acevedo B et al (Fertil & Steril 2004; 82:343-7) Randomized controlled study in donor cycles receiving either antagonist alone or antagonist with rLH A significant increase in MII oocyte (80% vs. 71%), fertilization rates (83% vs. 71%), G1 embryos (17% vs. 3%), and implantation rates (35% vs. 15%) in recipients whose embryos originated from donors receiving antagonist + rLH as compared to donors receiving antagonist alone E2 levels, pregnancy/transfer and clinical pregnancies were lower (not significant) in donors treated with antagonist alone vs. those receiving the rLH-supplemented antagonist

Controlled Studies on Agonist vs Antagonist - 1 Akman MA et al (Hum Reprod 2001, 16(5):868-70) Prospective randomized trial on poor responders: group 1 – agonistic flare-up protocol group 2 – antagonistic multi-dose protocol E2 levels on the day of hCG were lower in group 2 compared with group 1 Clinical pregnancy and implantation rates did not show any significant difference Limitation of this study: small sample size, with only 24 subjects in each group

Controlled Studies on Agonist vs Antagonist - 2 Vlaisavljevic V et al (Reprod Biomed Online 2003, 7(3):301-8) Prospective randomized study: group 1 – single dose long agonist (goserelin) protocol group 2 – single 3mg dose antagonist (cetrorelix) protocol, when the mean follicle diameter exceeded 12mm The mean number of ampoules of FSH and the duration of stimulation were statistically significantly lower in group 2 than in group 1 (25.9 versus 34.5, and 9.6 versus 12.2 days, P < 0.01) The mean number of oocytes retrieved, fertilization rates, blastulation rates and blastocyst transfer rates were similar in both groups Clinical pregnancy and delivery rates per cycle were higher in group 1 (34.3 and 30.1%) than in group 2 (31.9 and 28.3%), but the differences were not statistically significant

Controlled Studies on Agonist vs Antagonist - 3 Loutradis D. et al (Fertil & Steril 2004, 82(5):1446-8) Prospective randomized study: group A – long protocol of agonist group B – modified multi-dose antagonist protocol, starting when the largest follicle had reached 14mm, with simultaneous augmentation of 75IU rFSH up to and including the day of hCG administration No improved pregnancy and implantation rates

Meta-analysis on Agonist vs Antagonist - 1 Ludwig M, Katalinic A, Diedrich K (Arch Gynecol Obstet 2001; 265(4):175-82) A meta-analysis performed to evaluate whether there is a reduction in cases of severe OHSS and/or a reduction in pregnancy rates when using antagonists Cetrorelix but not ganirelix will reduce the incidence of cases of OHSS Cetrorelix but not ganirelix will result in the same pregnancy rates as the long agonist protocol

Meta-analysis on Agonist vs Antagonist - 2 Al-Inany H and Aboulghar M (Hum Reprod 2002; 17:874-85) A Cochrane review 5 randomized trials were included, comparing fixed protocol of antagonist with long protocol of GnRH agonist The clinical pregnancy rate was lower using antagonist No significant difference in prevention of premature LH surge and prevention of severe OHSS