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AMA and Poor Responder: A Challenge in IVF Program

This article discusses the challenges faced in IVF programs with advanced maternal age (AMA) and poor responders. It explores the factors affecting follicle recruitment and the decline in oocyte quality with age. The importance of oocyte/embryo quality and the role of stimulation regimens are highlighted. The potential of boosting intra-ovarian androgens and LH supplementation to improve follicle recruitment and pregnancy outcomes is also discussed.

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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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