The Role of Recombinant hCG in IVF
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This presentation discusses the role of recombinant human chorionic gonadotropin (hCG) in in vitro fertilization (IVF). It begins by outlining the learning objectives and providing background on hCG and its native and recombinant forms. The document then compares urinary and recombinant hCG, noting the higher purity and consistency of recombinant hCG. Several studies are summarized showing similar or improved outcomes with recombinant hCG compared to urinary hCG in terms of fertility measures like fertilization rates and pregnancy rates, as well as reduced risk of ovarian hyperstimulation syndrome.
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The Role of Recombinant hCG in IVF
- 1. 2nd SGH SOAR, Singapore 2014 The Role of Recombinant hCG in IVF Sandro C. Esteves, MD, PhD Medical Director, ANDROFERT Campinas, Brazil
- 2. Learning objectives At the completion of this presentation, participants should be able to: • Understand the differences between urinary and recombinant hCG • Learn the clinical advantages of rec-hCG in IVF as used for oocyte maturation triggering • Be aware of the additional potential use of rec-hCG in other IVF-related conditions ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2014 SEPTEMBER
- 3. Human Chorionic Gonadotropin • Glycoprotein produced during pregnancy by syncytiotrophoblast cells and by the pituitary in menopause women • In early pregnancy, hCG rescues the corpus luteum and maintains progesterone production until placental steroidogenesis is established ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2014 SEPTEMBER
- 4. In IVF, hCG administration has been the gold standard for final follicular maturation as a surrogate for the mid-cycle LH surge LH hCG Extracellular fluid Plasma membrane Cytoplasm LH/hCG receptor ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2014 SEPTEMBER
- 5. Native LH and hCG are not identical “sisters” LH hCG No. AA beta subunit 121 145 Receptor binding affinity Low High* No. glycosylation sites1 1 6 Half-life (t ½) 20-30 min 24h Bioequivalency 6 – 8 IU 1 IU 1N-linked and O-linked glycosylation sites in beta subunit *2-3x higher than LH Leao & Esteves. Clinics 2014;69:279-93. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2014 SEPTEMBER
- 6. hCG and IVF - History • Zondek & Ascheim (1927) found that urine of pregnant women contained a substance capable of inducing follicular maturation and ovarian stromal luteinization • First hCG preparations developed in 1931 from urine of pregnant women ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2014 SEPTEMBER
- 7. Urinary hCG production The source: • Pooled urine from pregnant women The process: • Urine pool is processed to concentrate gonadotropins • hCG is extracted and purified by either antibody affinity column or conventional chromatography ANDROFERT androfert.com.br Source: Dr. Shelley Slaughter, FDA ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2014 SEPTEMBER
- 8. Quantification of hCG activity based on rat ovarian weight gain Randomized 21-22 day old female rats hCG injected sc 1x for 3 days Sacrifice day 4 and collect ovaries Ovaries are weighed and data processed ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2014 SEPTEMBER Steelman & Pohley Endocrinol. 53:604-16, 1953
- 9. Level of functionally intact hCG and contamination among formulations Proportion of total immunoreactivity (%) Pregnyl® Choragon® Profasi® Intact bioactive hCG 50 30 96 Hyperglycosylated hCG 0.6 4 0.5 Free β subunit 6.2 8 2.4 β-core fragment1 43 58 1.2 Epidermal growth factor2 181-204 154 4-10 Yarram et al. Fertil Steril 2004;82:232-3 1degradation product of hCG; 2EGF is a contaminant (ng/5000IU) ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2014 SEPTEMBER
- 10. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2014 SEPTEMBER Non-gonadotropin proteins identified in u-hCG products PLoS ONE 2011; 6(3): e17815
- 11. What is the ideal gonadotropin preparation? • Originating from a safe and consistent source • Manufactured using consistent and standardized processes • Fully physiochemically characterized • Effective • Favorable safety profile • Patient-convenient ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2014 SEPTEMBER
- 12. 2001: rec-hCG (Choriogonadotropin alfa) Adapted from Leao & Esteves. Clinics 2014;69:279-93 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2014 SEPTEMBER
- 13. Secretion of hCG molecules Incorporation into host cell chromosome Bulk hCG Released Bulk hCG ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2014 SEPTEMBER
- 14. Purity (hCG content) Specific activity (hCG/mg protein)1,2 Protein/IU (mcg = IU) u-hCG <70% ~13,500 IU/mg ~550 = 5000 rec-hCG 99.9% 27,000 IU/mg 250 = 6750 u- hCG rec- hCG CG beta Contaminants CG alpha 1Bassett R et al Current Med Res Opinion 2005, 21:1969-76; 2Stenman U-H et al Br J Pharmacol 2008; 154:569-83; Van Dorsselaer A et al PLoS One. 2011;6:e17815 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2014 SEPTEMBER
- 15. Size Exclusion High Performance Liquid Chromatography (SE- HPLC) Filled by Mass Approach Proven consistency of rec-hCG physiochemical characteristics Consistent specific activity i.e. the same biological activity measured in IU/mg of protein Approval to fill (vials, pens) by mass (protein content in solution) Gervais et al. Glycobiology 2003;13:179-189; Leao & Esteves Clinics 2014;69:279-93. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2014 SEPTEMBER
- 16. rec- hCG u- hCG: lyophilized powder to be reconstituted ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2014 SEPTEMBER
- 17. Differences between urinary and recombinant hCG Key points Rec-hCG has higher purity and better safety profile compared with u-hCG Consistent physiochemical characteristics allow rec-hCG to be filled by mass, thus offering better dose precision and low batch-to-batch variation compared with u-hCG (filled by bioassay) High specific activity of rec-hCG allows SC administration using a pre-filled syringe or a pen device while u-hCG needs to be reconstituted and is primarily indicated for IM route ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2014 SEPTEMBER
- 18. Clinical advantages of rec-hCG in IVF as used for oocyte maturation triggering
- 19. Approved for use in the treatment of: • Adult women undergoing superovulation prior to ART such as IVF to trigger final follicular maturation and luteinization after stimulation of follicular growth; • Anovulatory of oligo-ovulatory women to trigger ovulation and luteinization after stimulation of follicular growth. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2014 SEPTEMBER
- 20. 250 μg rhCG=6,500 IU; SC 5,000 IU uhCG; IM 10,000 IU uhCG; IM Serum hCG levels Trinchard-Lugan et al., 2002 Itskovitz et al., 1991 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2014 SEPTEMBER
- 21. 0% 20% 40% 60% 80% 100% Patients Nurses Doctors & embryologists Safety Effectiveness Patient-centeredness Hum Reprod 2013;26(6):1584-97 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2014 SEPTEMBER
- 22. r-hCG (250 mcg) r-hCG (500 mcg) u-hCG (10,000 IU) No. patients 94 89 92 Oocytes retrieved (mean) 13.6 14.6 13.7 2PN fertilized (mean) 7.2 8.8 P=0.02 7.8 Serum P (d6-7 after hCG) 133.0 163.5 P=0.03 147.4 Pregnancy rate (%) 35.1 36 35.9 OHSS (%) 3.2 9.0 3.1 Chang et al. Fertil Steril. 2001; 76: 67–74 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2014 SEPTEMBER
- 23. RCT N Effect Oocytes retrieved 9 1409 MD: -0.04 (95% CI -0.69 to 0.61) Live birth 6 1,019 OR: 1.04 (95% CI 0.79 to 1.37) Miscarriage 7 1,106 OR: 0.69 (95% CI 0.41 to 1.18) Severe OHSS 3 549 OR: 1.49 (95% CI 0.54 to 4.1) Databases searched up to January 2010 Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2014 SEPTEMBER
- 24. *p<0.01 Farrag et al. JARG 2008; 25:461-6. ANDROFERT androfert.com.br 8.4 7.17.3 10 8 6 4 2 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2014 SEPTEMBER 4.7 0 No. Retrieved oocytes No. MII with mature cytoplasm rec-hCG (250 mcg; n=42) u-hCG (10,000 IU; n=47) *
- 25. Effectiveness RCT comparing rec-hCG (250 mcg) with u-hCG (10,000 IU) for oocyte maturation triggering on delivery rates in eSET antagonist cycles 10,000 IU u-hCG 250 mcg rec-hCG 26.7% 44.1% Delivery rate (%) N=119 aged<32 OR: 2.16 (95% CI: 1.01-4.67; p=0.04) Papanikolaou EG et al. Fertil Steril 2010; 94:2902-4 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2014 SEPTEMBER
- 26. Urinary and rec-hCG differentially impact trophoblast differentiation • In vitro treatment of trophoblast cells with different hCG products • Phosporilation of EGC receptors after u-hCG treatment, but not with rec-hCG • Increased trophoblast invasion and syncytialization observed using EGF-free hCG (rec-hCG) compared with u-hCG (EGF-contaminated) Saleh L et al. Placenta. 2007;28(2-3):199-203 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2014 SEPTEMBER
- 27. RCT N Odds-ratio Local site reactions* rec-hCG vs. u-hCG 3 374 0.39 95% CI: 0.25 to 0.61 Driscoll et al. 2000: 27% vs 42% ERHCG Group 2000: 23% vs 45% Abdelmassih et al. 2005: 23% vs 45% * Pain and/or inflammation Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2014 SEPTEMBER
- 28. Human errors after hCG administration • 0.5%-0.8% Empty follicle syndrome after u-hCG administration1,2 • Case report of patient who injected only diluent3 • Recurrent empty follicle syndrome successfully treated with rec-hCG4 1Quintans et al. Hum Reprod 1998;13:2703-5; 2Zegers Hochschild et al. Hum Reprod 1995;10:2262-5; 3Esposito & Patrizio J Reprod Med 2000;45:511-4; 4Penarrubia et al. Hum Reprod 1999;14:1703-6. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2014 SEPTEMBER
- 29. hCG preferences in treatment-experienced patients at Androfert Total (n=76) 60% 29% 3% 8% prefer new pen prefer pre-filled syringe prefer lyophilized powder to reconstitute Not matter ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2014 SEPTEMBER
- 30. Clinical advantages of rec-hCG in IVF for oocyte maturation triggering Key points • Safety originates from a safe and consistent contamination-free source; fully characterized • Effectiveness 250 mcg rec-hCG at least as effective as 10,000 IU u-hCG for final follicular maturation • Patient-centeredness better tolerated and preferred by treatment-experienced patients ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2014 SEPTEMBER
- 31. Additional possibilities for using rec-hCG in IVF • Male Infertility • Luteal phase support • Intrauterine administration
- 32. hCG in non-obstructive azoospermia prior to sperm retrieval Microdissection TESE • Rescue ~15% of patients with failed SR attempts1 1Shiraishi et al Hum Reprod 2012;27(2):331-9; Esteves Int Braz J Urol 2013;39(3):440 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2014 SEPTEMBER
- 33. Modified LPS for fresh ET in GnRH-a trigger using hCG No. follicles day OPU 1,500 IU hCG at OPU & 1,000 ≤ 14 OPU+5 & standard LPS 1,500 IU hCG at OPU + 15-25 standard LPS 1,000 IU hCG at OPU + 26-30 standard LPS or Freeze all >30 Freeze all 14h 14h LH Surge 20h 0 20 h 48h 4h GnRHa Natural Luteal phase defect Humaidan et al. Hum Reprod. 2013;28(9):2511-21 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2014 SEPTEMBER
- 34. Intrauterine hCG administration (500 IU) before embryo transfer Positive effect on endometrial receptivity1 • Inhibition of IGF-binding protein 1 and M-CFS • Stimulation of LIF, VEGF, MMP-9 Improvement in implantation and pregnancy rates 1Licht et al Hum Reprod Update 1998; 2Mansour et al Fertil Steril 2011; 3Santibañez et al Reprod Biol Endocrinol 2014 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2014 SEPTEMBER
- 35. Additional possibilities for using rec-hCG in IVF Key points Rec-hCG produces pharmacodynamic responses consistent with hCG physiology, thus offering the opportunity for use in the same clinical situations as u-hCG The secure source and high purity of rec-hCG may offer advantages when used for male infertility, luteal support and intrauterine administration Although preliminary data seems promising, safety, effectiveness and patient-centeredness still need to be evaluated in large RCT trials ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2014 SEPTEMBER