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Agonist vs Antagonist. Dr. Milton Leong. Gonadotrophin releasing hormone analogs. GnRH analogs: GnRH-like molecules 2 types of GnRHa: agonists and antagonists

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agonist vs antagonist

Agonist vs Antagonist

Dr. Milton Leong

gonadotrophin releasing hormone analogs
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
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
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
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
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
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
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
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
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
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
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