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Dr. Milton Leong Director

Dr. Milton Leong Director. IVF CENTRE Hong Kong Sanatorium & Hospital. The Gonadotrophin Releasing Hormone Antagonists. Synthesis of GnRH. pGlu1-His2-Trp3-Ser4-Tyr5-Gly6-Leu7-Arg8- Pro9-Gly10NH 2 by Schally in 1968

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Dr. Milton Leong Director

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  1. Dr. Milton Leong Director IVFCENTRE Hong Kong Sanatorium & Hospital

  2. The Gonadotrophin Releasing Hormone Antagonists

  3. Synthesis of GnRH • pGlu1-His2-Trp3-Ser4-Tyr5-Gly6-Leu7-Arg8- Pro9-Gly10NH2 by Schally in 1968 • GnRH could restore ovulatory functions in hypogonadotrophic amenorrheas. Schally AV, Arimura A, Bowers CY et al. 1968

  4. modifications of natural GnRH to have GnRH agonistic properties 1 2 3 4 5 6 7 8 9 10 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 regulation of GnRH receptor affinity regulation of biologic activity activation of the GnRH receptor Structure of GnRH agonists

  5. Premature LH surge • Poor quality • No fertilization or very poor pregnancy rate • Cancel egg retrieval 5-20% All cycles treated in 1980’s

  6. Results of first application of GnRH-agonists in the long protocol • 11 patients eligible for IVF • GnRH agonist s.c. (buserelin) started at day of menstruation or one day before • ovarian stimulation started with HMG or purified FSH when all ovarian follicles and the endometrial lining has disappeared on ultrasound (average: 15 days) • one ongoing pregnancy achieved Porter et al., 1984

  7. ovulation induction embryo transfer oocyte pick up gonadotropin administration in an individualized dosage 22nd day of previous cycle 1st day of gonado- tropins 14 days The long luteal protocol start of GnRH agonist luteal phase support

  8. Action of GnRH agonists downregulation GnRH LH + FSH GnRH - receptor post-receptor-cascade GnRH - agonist pituitary suppression flare up effect

  9. GnRH agonist Over-suppression: • LH becomes so low that it affects the production of estrogen, and possibly progesterone in the luteal phase • Leads to poor response, poor pregnancy outcome due to early abortion Also it is: • Too long and too much drug use, cost, cancelled cycles and it is unnatural.

  10. 1 2 3 4 5 6 7 8 9 10 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 regulation of GnRH receptor affinity regulation of biologic activity activation of the GnRH receptor Structure of GnRH antagonists to achieve antagonistic properties of natural GnRH more modifications than only in position 6 and 10 are necessary

  11. Action of GnRH antagonists GnRH LH + FSH GnRH - receptor post-receptor-cascade GnRH - antagonist pituitary suppression

  12. Structure of GnRH antagonists

  13. Ganirelix Fully effective within 4 hours, with a half-life of about 13 hours Cetrorelix Fully effective within 8 hours, with a half-life of about 36 hours Characteristics of GnRH R.E. Felberbaum and K. Diedrich, 1999.

  14. Antagonists in controlled ovarian stimulation - the first steps control Days relative to ovulation Nal-Glu cycles Ditkoff et al., 1991

  15. Cetrotide® Cetrorelix

  16. Dose finding studies to identify the minimal effective dose in the multiple dose and single dose protocol

  17. The development of the multiple dose antagonist protocol • 20 patients in IVF cycles • gonadotropins were started on cycle day 2 • Cetrorelix in a daily dosage of either 3 mg or 1 mg started on day 7 of stimulation • no spontaneous LH surge was observed Diedrich et al., 1994

  18. The development of the multiple dose antagonist protocol • dose finding study using Cetrorelix in a daily dosage of 3 mg, 1 mg, and 0.5 mg • no premature LH surge Felberbaum et al., 1996

  19. The development of the multiple dose antagonist protocol • dose finding study using Cetrorelix in a daily dosage of 0.5 mg, 0.25 mg, and 0.1 mg • premature LH surge occured in the 0.1 mg group Albano et al., 1997

  20. The development of the multiple dose antagonist protocol Cetrotide® 0.25 mg is the minimal effective dose in the multiple dose antagonist protocol

  21. The development of the single dose antagonist protocol • 11 patients for IVF • first injection of 3 mg Cetrorelix always on day 8 of the cycle • second injection, if no hCG injection latest 72 hours later possible • 3 patients received a second injection of Cetrorelix • these 3 patients had low estradiol levels on day of first Cetrorelix administration Olivennes et al., 1995

  22. The development of the single dose antagonist protocol Cetrotide® 3 mg is the minimal effective dose in the single dose antagonist protocol

  23. Dose Finding Studies With Ganirelix : • 2 mg, 1 mg, 0.5 mg, 0.25 mg, 0.125 mg and 0.0625 mg were used • 0.25 mg daily was the preferred dosage • With Ganirelix, increasing dosage related with drop in pregnancy rate and increase in abortion rate. • 2 mg daily dosage slowed follicular growth as well as almost stopping ay increase in estradiol secretion. The Ganirelix dose-finding Study Group, Hum Reprod 1998;13:3023-31

  24. no cyst formation no hormonal withdrawal early pregnancy? more physiologic less gona- dotropins longer treatment antagonist administration multiple dose protocol gonadotropin administration gonadotropin administration long protocol agonist administration Comparison of the long protocol and the antagonist protocols flare up effect pituitary suppression pre-treatment cycle treatment cycle

  25. Comparison of antagonist protocols and the long luteal protocolProspective, randomized trials

  26. The multiple dose antagonist protocol compared to the long luteal protocol • Prospective, randomized phase III study • 7 European centres • 273 patients for IVF or IVF/ICSI • Stimulation procedures • long luteal protocol: buserelin nasal spray (4 x 150µg) • multiple dose antagonist protocol: Cetrotide® 0.25 mg • start with 150 IU FSH per day in the antagonist and agonist group Albano et al., 2000

  27. The multiple dose antagonist protocol compared to the long luteal protocol • inclusion criteria • age: 18 - 39 years • normal menstrual cycle (range: 24 - 35 days) with an intraindividual variation of max. ± 3 days • no more than 3 IVF procedures • normal uterus and at least one functioning ovary • exclusion criteria • severe endometriosis (AFS III/IV) • PCO syndrome Albano et al., 2000

  28. The multiple dose antagonist protocol compared to the long luteal protocol n.s. not significant Albano et al., 2000

  29. The multiple dose antagonist protocol compared to the long luteal protocol n.s. not significant Albano et al., 2000

  30. The multiple dose antagonist protocol compared to the long luteal protocol n.s. not significant Albano et al., 2000

  31. The multiple dose antagonist protocol compared to the long luteal protocol:significant reduction of OHSS * p = 0.03, Fishers exact test, relative risk: 6.2 (95% CI: 1.4 - 27.1) Ludwig et al., 2000

  32. The multiple dose antagonist protocol compared to the long luteal protocol • Significantly less OHSS °II and °III(RR 6.2, 95% CI: 1.4 - 27.1, p = 0.03) • Less patients with threatened OHSS (no hCG - administration when  12 follicles  15 mm and/or estradiol  4.000 pg/ml) • Cetrotide® 0.25: 3 patients (1.6%) • buserelin: 5 patients (5.9%) • One more patient in the buserelin group did not have an embryo transfer because of a threatened OHSS Ludwig et al., 2000

  33. The multiple dose antagonist protocol compared to the long luteal protocol Ganirelix vs. Buserelin

  34. The multiple dose antagonist protocol compared to the long luteal protocol Ganirelix vs. Buserelin

  35. The multiple dose antagonist protocol compared to the long luteal protocolCetrorelix vs. Triptorelin depot

  36. The multiple dose antagonist protocol compared to the long luteal protocolCetrorelix vs. Triptorelin depot

  37. Reduction of OHSS using Cetrotide® • Multiple dose protocol • rate of OHSS: 6.5% vs. 1.1% (agonist vs. antagonist protocol) • RR 6.2, 95% CI: 1.4 - 27.1, p = 0.03 • Single dose protocol • rate of OHSS: 11.1% vs. 3.5% (agonist vs. antagonist protocol)95% CI: - 18.4 to 3.2 • patients requiring hospitalisation: 5.6% vs. 1.8% (agonist vs. antagonist protocol)95% CI: - 11.7 to 4.1 • With both Cetrotide® protocols a clear reduction of OHSS was be achieved

  38. Personal experience with multiple dose of Cetrorelix 0.25 mg Patient group: • Over suppression with agonist long protocol (LH < 1mlU) • Patient over 40 • Poor response to agonists suppression

  39. ovulation induction embryo transfer oocyte pick up gonadotropin administration in an individualized dosage 1st day of gonado- tropins Cetrotide® 0.25 mg administration daily s.c. starting on day 6 of stimulation The Cetrotide® 0.25 mg multiple dose protocol 1st day of menstruation luteal phase support

  40. Results Check the stimulation day 7th LH level • LH > 1.5 mIU/ml, 0.25 mg daily was given • LH < 1.5 mIU/ml, reduce to 0.125 mg daily Switching to a half dosage of 0.125 ml per day gives: • Normal LH levels • Expected follicular growth • Better ovum quality No premature LH surge or progesterone rise

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