Principles and Practices of LH Use in ART
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This document summarizes the principles and practices of LH administration in assisted reproductive technology (ART). It discusses the role of LH in reproductive cycles, patient subgroups that may benefit from LH supplementation, and differences in LH supplementation using various gonadotropin preparations. Specifically, it finds that LH supplementation can benefit older patients, poor responders, and hypo-responders by restoring androgen production and improving follicular development, oocyte quality, and pregnancy rates.
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Principles and Practices of LH Use in ART
- 1. Principles and Practices of LH administration in ART Sandro C. Esteves, MD., PhD. Medical Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, BRAZIL
- 2. Learning objectives At the completion of this presentation, participants should be able to: 1. Understand the role of LH in reproductive cycles 2. Identify patient subgroups to whom LH supplementation is beneficial 3. Appraise the differences in LH supplementation using the available gonadotropin preparations ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2015 ANDROFERT
- 3. Principles and Practices of LH administration in ART Kingdom of Saudi Arabia 2014 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2015 ANDROFERT This presentation is available at http://www.slideshare.net/ sandroesteves
- 4. Is LH important in reproductive cycles? a. True b. Maybe true c. False ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2015 ANDROFERT
- 5. 0 9 Endometrium (mm) 0 5 10 15 0 5 10 15 20 Days of Stimulation 50 100 Folliclesize(mm) andFSH(IU/L) ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2015 ANDROFERT
- 6. WHO type I treated with r-hFSH (150 IU) + r-hLH (75 IU) in a 2:1 ratio combination 17 patients; 27 cycles IU FSH ± SEM 1922 ± 266 IU LH ± SEM 961 ± 133 Days stimulation ± SEM 13.8 ± 1.8 % PR cycle 55.5% % PR patient 88.3% N follicles >17mm ± SEM 4.3 ± 2.4 E2 hCG day (pmol/l) 541 ± 299 Mid-luteal P4 (nmol/l) 40 ± 14 Endometrium sd10 (mm) 11 ± 3 E2/follicle (pmol/l) 152 ± 64 Carone et al. J Endocrinol Invest 2012 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2015 ANDROFERT
- 7. Early follicular phase Steroidogenesis (TC) Late follicular phase Steroidogenesis (TC) Up-regulates FSHr expression (GC) Sustains follicular growth and final follicular maturation (GC) Physiology of LH in reproductive cycles ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2015 ANDROFERT
- 8. Balasch & Fábreques 2002 • Adequate androgen and estrogen biosynthesis • Normal follicular development and oocyte maturation Normal • Follicular atresia • Premature luteinization • Oocyte development compromised High • Low (and estrogen) synthesis • Impaired follicular maturation • Inadequate endometrial proliferation Low LH Window ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2015 ANDROFERT
- 9. What is the minimum needed LH level? SerumLHUI/L 1.5 1.0 0.5 0.5 Westergaard 2001 0.7 Fleming 1998 1.2 O’Dea 2000 1.35 Mahmoud 2001 Injected rec-hLH LH Cmax 75 IU 0.5 – 1.35 IU/L ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2015 ANDROFERT
- 10. Is LH important in reproductive cycles? ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2015 ANDROFERT a. True b. Maybe true c. False
- 11. Who need LH supplementation during ovarian stimulation? a. All patients b. Poor responders c. Hypo-responders d. Older women (>35) e. GnRH antagonist protocol ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2015 ANDROFERT
- 12. u Natural cycle 5.4 3.1 1.68 0.75 0 1 2 3 4 5 6 SerumLHIU/l Sd1 Sd8 hCG OPU 0.15 GnRH agonist Hypo-hypo GnRH antagonist LH levels in natural and stimulated cycles 1.6 4.8 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2015 ANDROFERT
- 13. Among patients treated with FSH and GnRH analogues for IVF, is the addition of rec-LH associated with the probability of live birth? 0.01 0.1 10 100 Study FSH + LH FSH OR (fixed) Weight OR (fixed) n/N n/N 95% CI % 95% CI Agonist Sills 1999 3/13 10/17 10.00 0.21 [0.04, 1.05] Balasch 2001 0/16 1/14 2.32 0.27 [0.01, 7.25] Humaidan 2004 39/116 31/115 31.00 1.37 [0.78, 2.41] Fabregues 2006 24/60 25/60 22.50 0.93 [0.45, 1.93] Tarlatzis 2006 6/55 10/59 12.90 0.60 [0.20, 1.78] Subtotal (95% CI) 72/260 77/265 78.72 0.94 [0.64,1.39] Antagonist Sauer 2004 9/25 10/24 9.80 0.79 [0.25, 2.49] Griesinger 2005 8/62 9/65 11.48 0.92 [0.33, 2.56] Subtotal (95% CI) 17/87 19/89 21.28 0.86 [0.40,1.85] Total (95% CI) 89/347 96/354 100.00 ] advantage r-hFSH Advantage r-hFSH + r-hLH Unselected Patient Population Kolibianakis, et al. Hum Reprod Update 2007;13:445-452 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2015 ANDROFERT
- 14. Is LH needed in unselected women treated with FSH and GnRH antagonists in IVF? Mochtar et al. 3 RCT (N=216) Baruffi et al. 5 RCT (N= 434) Estradiol on hCG day (pg/ml) WMD 571 (95% CI 259; 882) WMD 514 (95% CI 368; 660) No. retrieved oocytes WMD 0.50 (95% CI -0.68; 1.68) WMD 0.41 (95% CI -0.44; 1.3) CPR†/LBR* †OR 0.79 (95% CI: 0.26; 2.43) †OR 0.89 (95% CI: 0.57; 1.39) Mochtar et al. Cochrane Database Syst Rev. 2007;2:CD005070; Baruffi et al, Reprod Biomed Online. 2007;14:14-25. WMD weight mean difference ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2015 ANDROFERT
- 15. Impaired oocyte quality Decreased fertilization rate Reduced embryo quality Increased miscarriage rates Reduced ovarian paracrine activity Hurwitz & Santoro 2004 Androgen secretory capacity reduced Piltonen et al., 2003 Decreased number of functional LH receptors Vihko et al. 1996 Reduced LH bioactivity Mitchell et al. 1995; Marama et al 1984 3-5 in every 10 treated women have aged ovaries ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2015 ANDROFERT
- 16. Bioactive LH Levels 30-45% have less sensitive ovaries Older patients (≥35 years)3 Poor responders4 Slow/Hypo-responders5 Deeply suppressed endogenous LH levels (hypo-hypo; endometriosis treated with GnRH-a)6 Low 1Tarlatzis et al. Hum Reprod 2006; 2Esteves et al. Reprod Biol Endocrinol 2009; 3Marrs et al. Reprod Biomed Online 2004;4Mochtar MH, Cochrane Database, 2007; 5Alviggi, et al. RBMOnline 2009; 6De Placido et al. Clin Endocrinol (Oxf) 2004 Normal ~55-70% normogonadotropic women undergoing COS1,2 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015 ANDROFERT
- 17. AGE
- 18. LH supplementation improves clinical pregnancy in women >35 yo. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2015 ANDROFERT
- 19. Fertil Steril 2011 Implantation rate(%) p=0.03 OR: 1.56 (1.04-2.33) p=0.84 OR: 1.03 (0.73-1.47) 27.8 18.9 28.6 26.7 <=35 36-39 r-FSH + r-hLH* ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2015 ANDROFERT *75 IU r-hLH form Sd1
- 20. Poor responders
- 21. Pregnancy rates increased by 30% in poor responders treated with rLH+rFSH Lehert et al Reprod Biol Endocrinol 2014, 12:17 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2015 ANDROFERT
- 22. Lehert et al 2012 Significant increase of +0.75 oocytes in poor responders treated with r-hFSH + r-hLH Lehert et al Reprod Biol Endocrinol 2014, 12:17 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2015 ANDROFERT
- 23. 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 20 25 30 35 40 Livebirthrate(%) Oocyte number Observed live birth rate Predicted live birth rate Sunkara et al. Hum. Reprod., 2011 400,135 IVF cycles Number of Oocytes and LBR ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015 ANDROFERT
- 24. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2015 ANDROFERT
- 25. On average, one additional embryo for transfer or cryopreservation Air Quality Control and GMP 2,315 patients; 14,660 embryos ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015 ANDROFERT
- 26. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2015 ANDROFERT Why is LH beneficial in aged women and poor responders? Total Testosterone ↓ 55% DHEAS ↓ 77% Free Testosterone ↓ 49% Androstenedione ↓ 64% n = 1423 Davison SL et al JCEM 2005;90:3847
- 27. • Action of LH at the follicular level in a dose dependent manner increases androgen production • Androgens are then aromatized to estrogens and help restore the follicular milieu Rationale of LH supplementation (1) ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2015 ANDROFERT
- 28. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2015 ANDROFERT Rationale of LH supplementation (2) Anti-apoptotic effect on granulosa cells Up-regulate growth factors Increase FSH receptor responsiveness Act synergistically with IGF-1 Rimon E et al., 2004; Robinson RS et al., 2007; Tilly JL et al., 1992; Peluso JJ et al., 2001, Ben-Ami I et al., 2009
- 29. Hypo Responders
- 30. Definition of hypo-responders (initial poor responders) Alviggi et al. RBM online 2006; 2009 • Normal ovarian reserve • May present follicular growth plateau on D7-D10 • Achieve ‘adequate’ number of oocytes retrieved and estradiol production • But at the expense of an increased cumulative rFSH dose (i.e. >3000 IU) and duration of stimulation ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2015 ANDROFERT
- 31. Why is there a suboptimal response to exogenous FSH in hypo-responders? LH gene polymorphism: V-LHβ Carrier frequency 0-52% in various ethnic groups ü 13 % in Sweden ü 12-13 % in Denmark and Italy Associated with reduced bioactivity of LH Huhtaniemi et al., 1999; Jiang et al., 1999; Ropelato et al., 1999 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2015 ANDROFERT
- 32. The cumulative FSH consumption is higher in carriers of v-beta LH polymorphism Alviggi et al. Reproduc0ve Biology and Endocrinology, 2013 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2015 ANDROFERT
- 33. Hypo-responders benefit from LH Cochrane review 2007 Mochtar MH, Cochrane Database, 2007 issue 2 Favours r-hFSH Favours r-hFSH + r-hLH Ongoing PR per woman randomized (COS in a GnRH-agonist dow-regulated IVF/ICSI cycle) ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2015 ANDROFERT
- 34. 6 9 1110 14 18 22 32 40 FSH step-up (+150 UI) LH supplementation (Sd8) Normal Responders Mean No. oocytes retrieved IR (%) OPR (%) De Placido et al. Hum Reprod. 2004; 20: 390-6 RCT 260 pts. with “steady” response on stimulation D8 (E2 <180pg/mL; >6 follicles <10mm) LH supplementation in Hypo-responders ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2015 ANDROFERT
- 35. Who need LH supplementation during ovarian stimulation? a. All patients b. Poor responders c. Hypo-responders d. Older women (>35 yrs.) e. GnRH antagonist protocol ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2015 ANDROFERT
- 36. What product to use for LH supplementation? a. hMG/HP-hMG b. rec-hLH c. Either of the above; they are similar ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2015 ANDROFERT
- 37. Gonadotropins containing LH activity Adapted from: Leao & Esteves. Clinics 2014; 69(4): 279–293. Product LH activity (IU/vial) LH content* Purity hMG 75 hCG ~5% HP-hMG 75 hCG ~70% Lutroprin alfa (rec-hLH) 75 LH >99% Follitropin alfa + lutroprin alfa in a 2:1 ratio combination 75 LH >99% *hCG concentrated or added during purification process (8IU hCG ~ 75IU LH) ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2015 ANDROFERT
- 38. Fertil Steril 2012; 97(3): 561-72 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2015 ANDROFERT
- 39. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 39 2015 ANDROFERT Extracellular fluid Cytoplasm Plasma membrane LH hCG LH/hCG receptor Sharing the same α subunit and 81% of AA residues of β subunit, LH and hCG bind to the same receptor Adapted from: Leao & Esteves. Clinics 2014; 69(4): 279–293.
- 40. Structural characteristics, half-life in serum and downstream effects of LH and hCG following receptor binding LH hCG Aminoacid number Alpha subunit Beta subunit 92 121 92 145 N-linked glycosilation sites Alpha subunit Beta subunit 2 1 2 2 O-linked glycosilation sites -- 4 Carboxyl-terminal segment non-existent present Half-life (hours) Initial, range of mean Terminal, range of mean Terminal (SC injection) 0.6-1.3 9-12 21-24 3.9-5.5 23-31 72-96 Response ED50 (pM)1 Time to maximal cAMP accumulation1 ERK 1/2 activation2 AKT activation2 CYP19A1 expression in presence of ERK1/2 pathway blockade2 530.0 ± 51.2 10 min strong strong increased 107.1 ± 14.3 1 h weak minimal unaffected 1 Effect on COS-7/LHCGR cells that constitutively express LH receptors 2 Effect on human granulosa cells Esteves & Alviggi. Principles and practices of COS in ART, Springer 2015 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2015 ANDROFERT
- 41. Divergence in receptor-mediated signaling between LH and hCG Choi & Smitz Mol Cell Endocrinol 2014; 383(1-2):203–13. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2015 ANDROFERT
- 42. • ERK/PKA & AKT cell survivor regulators and apoptosis blockers • P produc0on in preovulatory GCs mainly modulated by ERK/PKA • In vitro ac0va0on of cAMP pathway associated with apopto0c events ERK/PKA & AKT pathway (LH) cAMP (hCG) ERK/PKA & AKT pathways Casarini et al., 2012; Grzesik et al., 2014 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2015 ANDROFERT
- 43. • LH significanly more potent to induce EREG gene expression • Epiregulin plays a key role in oocyte matura:on Epiregulin (EREG) pathway Chin & Abayasekara, 2004; Sekiguchi et al., 2004 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 43 2015 ANDROFERT
- 44. 0" 20" 40" 60" 80" 100" 120" 2PN$ Preg.$ IR$ DNA$ fragmenta2on$ r4$FSH$ hMG$ r4FSH$+$r$LH$ *P<0.01 * * * Lower apoptosis rate (marker of oocyte quality) in human cumulus cells aQer administra0on of rec-‐LH to women undergoing COS for IVF Ruvolo et al. Fertil Steril 2007; 87:542-6 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 44 2015 ANDROFERT
- 45. • Cross-over study (n=66) comparing rec-hFSH + rec-hLH (2:1) vs. HP-hMG • All patients in rFSH+rLH group (vs. 1/3 hMG group) had frozen embryos to transfer if fresh transfer failed Fábregues F et al. Gynecol Endocrinol. 2013;29(5):430-5. Type of LH supplementation and number of oocytes retrieved 7.3 9.8 No. oocytes retrieved HP-HMG rec-FSH + rec-LH p<0.01 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 45 2015 ANDROFERT
- 46. 19 14 14 31 26 25 0 5 10 15 20 25 30 35 Fixed 2:1 r-hFSH (150IU)/r-hLH (75IU) HMG rec-hFSH + HMG Duration of Stimulation (days) Mean No. oocytes retrieved IR (%) CPR per transfer (%) Buhler KF, Fisher R. Gynecol Endocrinol 2011 Matched case-control study; N=4,719 IVF pts. P=0.02 Does it matter whether hMG hCG (hMG) or rec-hLH? ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 46 2015 ANDROFERT
- 47. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 47 2015 ANDROFERT
- 48. ü Significant differences exist between LH and hCG at boh the molecular and functional level ü Preliminary evidence indicates that the choice of products containing LH activity impact IVF clinical outcome What product to use for LH supplementation? Key points ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 48 2015 ANDROFERT
- 49. How we use LH supplementation at Androfert ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 49 2015 ANDROFERT
- 50. Ovarian stimulation protocol ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 50 2015 ANDROFERT
- 51. Population Cut-off Sensitivity Specificity Accuracy AMH* ng/ mL High- responder1 2.1 85% 79% 0.82 Poor responder2 0.82 76% 86% 0.88 *Beckman-Couter generation II assay; 1>20 oocytes retrieved; 2≤4 oocytes retrieved Leão RBF, Nakano FY, Esteves SC. Fertil Steril 2013; 100 (Suppl.): S16 Biomarkers of ovarian response AMH ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 51 2015 ANDROFERT
- 52. Rec-hFSH + rec-hLH (2:1 ratio) from Sd1 Gonadotropin dose per day 450 IU: Ø rec-hFSH 300 IU + rec-hLH 150 IU) GnRH antagonist (flexible): mean 13mm LH trigger with rec-hCG (mean 17-18 mm Our preferred regimen in expected poor responders (AMH≤0.82 and/or history of POR) 2 3 4 5 7 6 8 9 10 11 1 Menses 13 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 52 2015 ANDROFERT 12
- 53. Individualized vs. conventional COS in expected poor responders (N=118) 72.0 3.5 45.0 20.0 46.6 4.8 23.3 26.8 0 20 40 60 80 Observed Poor Response (%) Oocytes retrieved (N) Cancellation (%) Pregnancy/cycle (%) cCOS (Long GnRH with r-hFSH) iCOS (GnRH Antag. with r-hFSH+r-hLH) Expected poor response: AMH<0.82 ng/dL; Observed poor response <5 oocytes retrieved; Leão RBF, Nakano FY, Esteves SC. Fertil Steril 2013; 100 (Suppl.): S16. *p<0.05 * * * ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 53 2015 ANDROFERT
- 54. GnRH antagonist flexible protocol Rec-hFSH + rec-hLH (2:1 ratio) from Sd1 Gonadotropin dose/day 225 IU: Ø rec-hFSH 150 IU + rec-hLH 75 IU How tse LH in Coin SOur preferred regimen in women ≥35yr. and normal ovarian reserve (AMH>0.82) 2 3 4 5 7 6 8 9 10 1 Menses 13 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 54 2015 ANDROFERT 11 12
- 55. GnRH antagonist flexible protocol; i. r-hFSH + r-hLH (2:1 ratio) from Sd6-7 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 55 2015 ANDROFERT Our preference in hypo-responders (Age <35yr.; AMH >0.82; follicular stagnation (<10mm) Sd5-7) Gonadotropin dose per day: 225 IU 2 3 4 5 7 6 8 9 10 11 1 Menses 14 ii. r-hFSH + r-hLH (2:1 ratio) from Sd1 2 3 4 5 7 6 8 9 10 1 13 11 12 12 13
- 56. Expected poor responders § AMH ≤ 0.82 ng/ml § History of previous IVF a_empt with poor response at a conven0onal s0mula0on Hypo responders § < 35 yr. § AMH >0.82 ng/ml § Follicular stagna0on aQer 6-‐7 days of s0mula0on with r-‐ hFSH 2 Start from Sd6-‐7 (1st cycle) Start Sd1 (subsequent cycles) (1 vial/day) Start from s0mula0on day 1 (2 vials/day) Our strategy for LH supplementa0on using 2:1 combina0on of r-‐hFSH + r-‐hLH § Expected normo-‐ responder (AMH >0.82 ng/ml and no history POR) Age ≥ 35 Start from s0mula0on day 1 (1 vial/day) 3 1 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 56 2015 ANDROFERT
- 57. 40.4% 48.0% ET #3 (FET) 49 ET #2 (FET) 239 ET #1 (fresh) 822 50.5% +18.8% +25.0% Female Age ≤39 ANDROFERT 332/822 63/239 17/49 Cumulative LBR – IVF/ICSI Year 2012 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 57 2015 ANDROFERT
- 58. Conclusions 1. Adequate LH levels critical for steroidogenesis, follicular development and oocyte maturation 2. Androgen secretory capacity decreases with ovarian aging Mechanisms include decreased number of functional LH receptors and ovarian paracrine activity. LHr polymorphisms involved in hypo-responders ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 58 2015 ANDROFERT
- 59. 3. Patients most likely to benefit from 2:1 fixed FSH/LH combination during COS: Poor/hypo responders Age >35 years; hypo-hypo 4. rec-hLH and hMG sources of LH- acitivity LH and hCG differ at molecular and functional levels 5. iCOS with 2:1 FSH/LH combination has been one of our strategies to maximize success in IVF ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 59 2015 ANDROFERT Conclusions