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AMA and Poor Responder: A Challenge in IVF Program

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  1. “AMA and Poor Responder”A Challenge in IVF Program CGH-Taipei Dr.SC Chen

  2. ART 不可缺之三元素 • Sperm – ICSI – Donor Insemination • Oocyte – COH Strategy – Egg donation • Uterus - Surgery – Surrogacy

  3. Poor Responders • 定義 ≤3 follicles in Response to COH • AMA • Young Poor Responder

  4. Follicle Recruitment • Young Girl - >1000/month • Chlidbearing – 500/month • >35ys – 100/month

  5. Gonadotrophin dependent phase of growth Growth Phase How to reverse the age related decline? • Act before , during or after the recruitment phase

  6. Reduced Quality of Oocytes • Increase in Aneuploidy (Munne et al 1995) • Reduced Mitochondrial DNA(May – Panloup et al 2005) • →Low Potential for Implantation & Successful Delivery of a Live Birth

  7. Outcome of IVF in Women 45Years Older • 30%Cancellation Rate (70/231) • Overall PR 21.1%(34/161)Per Retrieval • 85.3%(29/34)Experienced a Pregnancy Loss • Overall Delivery Rate Was 3.1%(5/161) Steven D. Spandorfer Zev Rosenwaks Jan 2007

  8. Oocyte / Embryo quality is always the most important key to successful pregnancy. • Type of stimulation regimen plays an important role .

  9. Gn : HMG, metrodin-HP,r-FSH,r-LH • GnRHa : agonist & antagonist, Long Vs Short protocol

  10. theca granulosa Androgens have a Paracrine action in the Early Follicular Phase LH FSH + androgen (Hillier 2001)

  11. 2 0 Aromatase activity (ng E2/1000cells/3h 1 0 0 0 1 1 0 1 0 0 1 0 0 0 1 0 , 0 0 0 T e s t o s t e r o n e c o n c e n t r a t i o n ( n M ) (Hillier et al. 1998) Testosterone Enhances FSH-induced Granulosa Cell Gene Expression

  12. 300 250 200 * * * 150 * Total Follicle Number 100 50 0 Control T 3-Day T 10-Day Androgens Stimulate Early Stages of Follicular Growth in the Primate Ovary Treatment Group (Vendola et al. 1998)

  13. Boosting Intra Ovarian Androgens to improve follicle recruitment? • 43 normo-ovulatory women before IVF (OCP + GnRH agonist) • D3 DHEA : negatively correlated with FSH dose • D3 Testosterone : predictive of IVF cycle success T < 0.20 ng / ml - PR = 11.2 % T > 0.20 ng / ml - PR = 53.1 % • T after down regulation : inversely related to the gonadotropin dose & the days of stimulation Frattarelli et al (Fertil Steril 2004)

  14. Addition of r-LH Prior to r-FSH Stimulation or Pretreatment with Testosterone Prior to r-FSH Stimulation

  15. Boosting Intra Ovarian Androgens to improve follicle recruitment? • Addition of r-hLH PRIOR to r-hFSH stimulation in a Long Agonist Protocol (Benney et al unpublished) • Multicentre study in UK,France,Scandinavia using 300 IU LH for 7days PRIOR to FSH stimulation in normogonadotrophic patients • Pilot study using 150 IU/day for 5 days in normogonadotrophic women:-no difference in no. oocytes retrieved but rate of embryo development improved (P<0.005)

  16. DhCG S1 L1 r-hFSH 150 IU/day Depot GnRHAgonist R-hLH 300 IU/day for 7 days Pre-FSH treatment with R-hLH in ART patients (Fleming et al 2006) • When down regulation achieved (L1) patients scanned and blood sample then randomised to receive LH 300 IU/day for 7 days or continued on agonist • On S1 patients scanned, blood taken then Gonal-f 150 IU/day initiated

  17. p = 0.124 p = 0.010 10.7 11 10 FSH+LH < 35 9.3 8.3 FSH+LH  35 5 FSH < 35 FSH  35 0 ITT Primary Endpoint: Total MII Oocytes in < 35 and  35 Years Subgroup, by Treatment 9.3 FSH + LH FSH Marrs et al 2003 RBMonline 8 175-182

  18. Clinical Pregnancy rates were higher in AMA patients treated with r-hLH Marrs et al 2003 RBMonline 8 175-182 P= 0.027 * Older patients (>=35) undergoing 1st ART cycle and treated with r-hFSH + r-hLH had a significantly higher (P= 0.027) pregnancy rate than those receiving r-hFSH alone

  19. p = 0.05 Implantation rate improved in older women supplemented with LH • Humaidan et al.., 2004

  20. What is the mechanism by which LH supplementation may improve outcome in women of advanced maternal age? • Boost intrafollicular E2/T concentration with selective LH supplementation • Poor responders to FSH stimulation have low intra-follicular E2 /T and high P4 (Foong et al 2005) • Evidence for intra-follicular E2 playing a role in oocyte cytoplasmic maturation • In vitro E2 increases fertilization and cleavage rate (Tesarik & Mendoza 1995) • Higher intrafollicular E2 predictor of pregnancy (Mendoza 2002) • In bovine intra follicular E2 upregulates DNA repair enzymes (Murdoch & Van Kirk. 2001)

  21. Boosting Intra Ovarian Androgens to improve follicle recruitment? • Addition of r-hLH PRIOR to r-hFSH stimulation in a Long Agonist Protocol • Pre-treatment with Testosterone prior to r-hFSH stimulation S1 DhCG TESTOGEL GnRHAgonist/ r-hFSH 15 - 20 days

  22. Boosting Intra Ovarian Androgens to improve follicle recruitment? • Pre-treatment with Testosterone prior to r-hFSH stimulation (Massin et al 2004 ESHRE Abstract) • Low responders received transdermal Testosterone (10mg/day) for 15 days prior to FSH • No. MII oocytes and embryos increased in T group resulting in 25 vs 5% (placebo) clinical pregnancy rate

  23. Gonadotrophin dependent Growth Phase Improving follicle recruitment in AMA patients • Evidence from primates suggest that androgens can reduce apoptosis (Weil et al 1999) – more follicles enter recruitment phase – Balasch et al 2006 Apoptosis decreased?

  24. Effect of transdermal testosterone supplementation (Massin et al 2004) Placebo N=20 Testogel N=16 p Transfer(n) 18 12 Embryo transferred 1,65 ± 0,20 1,69 ± 0,33 NS Biological pregnancy (%) 3 (15%) 4 (25%) Clinical pregnancy (%) 1 (5%) 4 (25%) Delivery 1 2 9% (3/33) Implantation rate 15% (4/27)

  25. DHEA: Dehydroepiandrosterone • androgen precursor • ‘nutritional supplement’

  26. DHEA: • Mildly improves cycle stimulation parameters Casson et al: Human Reprod 2000; 15: 2129-32

  27. 43 year old women self medication with 75mg DHEA daily and acupuncture • Over 9 cycles of treatment the number of oocytes and embryos recovered increased

  28. Univariate comparison of results of in vitro fertilization before and after treatment with DHEA (Barad & Gleicher 2005) Protocol: Microdose GnRH agonist 600IU FSH starting dose before and after DHEA treatment DHEA pretreatment 25mg TID for average 28 weeks

  29. Summary • AMA & Poor Responder 的 management對臨床醫師是一項挑戰 • 給予(補充) LH 及 DHEA 是可行的方法 • 慎選case

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