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Carlo Alviggi

The use of r-hLH in IVF/ICSI cycles International Symposium on Reproductive Medicine -1 June 4 - 6, 2010 Istanbul, Turkey. Carlo Alviggi. Università degli studi di Napoli “Federico II” Centro di Sterilità ed Infertilità di Coppia Prof. G. De Placido.

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Carlo Alviggi

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  1. The use of r-hLH in IVF/ICSI cyclesInternational Symposium onReproductive Medicine -1June 4 - 6, 2010Istanbul, Turkey Carlo Alviggi Università degli studi di Napoli “Federico II” Centro di Sterilità ed Infertilità di Coppia Prof. G. De Placido

  2. LH levels during spontaneous and stimulated cycles LH during folliculogenesis • Since early follicular phase • Induction of androgens production in the theca cells Increase in follicular recruitment • Since intermediate follicular phase • (Expression of LH receptors in the granulosa) • Sustain of FSH-dependent granulosa activities, including aromatase induction and growth factors release (IGF-1, EGF etc…) • Optimization of steroidogenesis • Reduction of progesterone production (?) Paracrine activity

  3. Since intermediate follicular phase • (Expression of LH receptors in the granulosa) • Sustain of FSH-dependent granulosa activities, including aromatase induction and growth factors release (IGF-1, EGF etc…) • Optimization of steroidogenesis • Reduction of progesterone production (?) Paracrine activity Role of LH during intermediate folliculogenesis Who requires LH supplementation? All patients? Advaced reproductive age? Hyporesponders? Pharmacogenomics? Antagonists?

  4. Since intermediate follicular phase • (Expression of LH receptors in the granulosa) • Sustain of FSH-dependent granulosa activities, including aromatase induction and growth factors release (IGF-1, EGF etc…) • Optimization of steroidogenesis • Reduction of progesterone production (?) Paracrine activity Role of LH during intermediate folliculogenesis Who requires LH supplementation? All patients? Advaced reproductive age? Hyporesponders? Pharmacogenomics? Antagonists?

  5. Prospective randomised trials comparing the effect of drugs containing different rLH doses on ovarian/IVF outcomenormogonadotrophic women Alviggi et al. (modified), RBMOnline, 2006

  6. Kolibianakis EM et al., 2007 7 RCT’s (701 patients), among which 5 reported agonist and 2 antagonist cycles.

  7. Prospective randomised trials comparing the effect of drugs containing different rLH doses on ovarian/IVF outcomenormogonadotrophic women Overall analysis of the studies suggests that LH supplementation in unselected patients may represent an adjunctive cost which is not balanced by an adequate improvement in the ovarian/IVF outcome De Placido et al., Drugs, 2008

  8. Since intermediate follicular phase • (Expression of LH receptors in the granulosa) • Sustain of FSH-dependent granulosa activities, including aromatase induction and growth factors release (IGF-1, EGF etc…) • Optimization of steroidogenesis • Reduction of progesterone production (?) Paracrine activity Role of LH during intermediate folliculogenesis Who requires LH supplementation? All patients? Advaced reproductive age? Hyporesponders? Pharmacogenomics? Antagonists?

  9. R-hLH - IVF outcome according to age: retrospective-subgroup analysis from RCT <35 years + LH 35 years + LH <35 years - LH 35 years - LH Oocytes (no) 9.1 10.3 10.1 9.4 2PN (% per MII) 53.3 61.9 58.1 47.6 ET no (%) 81 (85.3) 19 (90.5) 86 (88.7) 17 (94.4) Pos. HCG (% per ET) 41/81 (50.6) 7/19 (36.8) 40/86 (46.5)A 4/17 (23.5)A IR % 30.8 36.4B 31.2G 13.3 B, G Clin. PR (% per cycle) 35/95 (36.8) 7/21 (33.3) 31/97 (32.0) 4/18 (22.2) A: p <0.05 (2 – test) B: p <0.05 (Fishers Exact test) G: p <0.05 (Fishers Exact test) Humaidan et al., RBMOnline 2004

  10. Mid-follicular LH supplementation in women aged 35–39 years undergoing ICSI cycles: a randomized controlled study Matorras et al., RBMOnline, 2009 RCT - 131 women (35 - 39 years) Long protocol, r-hFSH 200-450 IU - randomization on day 6 Group A (n = 68) = r-hFSH Group B (n = 63) = r-hFSH + r-hLH (150 IU)

  11. Mid-follicular LH supplementation in women aged 35–39 years undergoing ICSI cycles: a randomized controlled study Matorras et al., RBMOnline, 2009 RCT - 131 women (35 - 39 years) Long protocol, r-hFSH 200-450 IU - randomization on day 6

  12. Since intermediate follicular phase • (Expression of LH receptors in the granulosa) • Sustain of FSH-dependent granulosa activities, including aromatase induction and growth factors release (IGF-1, EGF etc…) • Optimization of steroidogenesis • Reduction of progesterone production (?) Paracrine activity Role of LH during intermediate folliculogenesis Who requires LH supplementation? All patients? Advaced reproductive age? Hyporesponders? Pharmacogenomics? Antagonists?

  13. Gonadotrophin-releasing hormone (GnRH) – a long protocol: different categories of ovarian response to FSH Normal response: >5 oocytesoestradiol 500–3000 pg/ml Poor response: <5 oocytes oestradiol <500 pg/ml High response: ‘necklace’ ultrasonography (USG) pattern oestradiol >3000 pg/ml – many eggs

  14. Hypo-response to rFSH Hypo-responders can achieve ‘adequate’ number of oocytes retrieved and oestradiol production BUT… There is an increase in the cumulative rFSH dose (i.e. >3000 IU) and in the stimulation length Reduction of the implantation and PRs De Placido et. al, Hum Reprod 2001, Clin Endocrinol 2004, Hum Reprod 2005; Drugs 2008 Ferraretti et. al, Fertil Steril 2004; Kailasam et. al, Hum Reprod2004 Alviggi et al., RBMOnline 2006; Devroey et al., Hum Reprod Update 2009

  15. GnRH – a long protocol: different categories of patients can be identified on the basis of ovarian reserve and clinical characteristics HYPO RESPONDER Normal responder 88–93% Ovarian response Poor responder 5–7% High responder 2–5%

  16. Hypo-respondersClinical evidence and pathogenesis rFSH 150–225 IU/day RCTs evaluated the efficacy of r-hLH vs increasing r-hFSH dose in women displaying initial slow-response to r-hFSH mono-therapy (De Placido et al., 2004; Ferraretti et al., 2004; De Placido et al., 2005) Is hypo-response related to a less bioactive LH? R-hLH vs r-hFSH step up Slow follicular growth DAYS 21 1 2 3 4 5 6 7 8 9 10 11 12 13 GnRH – a daily-depot

  17. Cochrane review 2007: Recombinant Luteinizing Hormone (rLH) for controlled ovarian hyperstimulation in assisted reproductive cycles Ongoing PR per woman randomized Favours r-hFSH + r-hLH Favours r-hFSH Mochtar MH, Cochrane Database, 2007, Issue 2

  18. Hypo-respondersClinical evidence and pathogenesis RCTs and one meta-analysis demonstrated that rLH supplementation is able to improve ovarian response and implantation rates in women displaying hypo-response to r-hFSH mono-therapy (De Placido et al., 2004; Ferraretti et al., 2004; De Placido et al., 2005; Mochtar, 2007) Is hypo-response related to a less bioactive LH? Hypo-responders benefit from r-LH independently of LH endogenous levels during stimulation Less bio-active LH?

  19. Since intermediate follicular phase • (Expression of LH receptors in the granulosa) • Sustain of FSH-dependent granulosa activities, including aromatase induction and growth factors release (IGF-1, EGF etc…) • Optimization of steroidogenesis • Reduction of progesterone production (?) Paracrine activity Role of LH during intermediate folliculogenesis Who requires LH supplementation? All patients? Advaced reproductive age? Hyporesponders? Pharmacogenomics? Antagonists?

  20. LH beta subunit variant The common Trp8Arg/Ile15Thr Y LH 30 b 121 1 Trp8Arg Ile15Thr additional sulphated sugar at asn-13

  21. Western India (Kota) Mexico (Mayan) Spain (Vasco) United States (Hispanic) Japan Jordan Thailand Italy Sweden (Göteborg) China The Netherlands United States (black) United Kingdom South Africa (black) Sweden (Stockholm) Poland Estonia Greenland Iceland Faroe Islands Finland Finland (Lapp) Australia/Aboriginals Worldwide occurrence of variant LH Percent V/V + V/WT 0 13.6% 0 10 20 30 40 50 60

  22. The common LH variant Structure - Function • Two amino acid changes in b-chain • Additional sulphation in b-chain • Increased in vitro bioactivity • Decreased circulatory half-life • Increased promoter activity Net effect…? • Association with ovulatory disorders and infertility Takahashi et al., Hum Reprod,1998

  23. LH gene polymorphism in women with ovarian resistance to rFSH • 60 patients screened for V-bLH • group A: 22 women requiring a cumulative dose of rFSH >3500 IU • group B: 15 patients requiring 2000-3500 IU • group C: 23 women requiring <2000 IU • 8 variants found Seven carriers of v-LH (2 homozygosis and 5 heterozygosis) were found in group A, whereas only one variant (heterozygosis) was found in group B; no variant was found in the group C Alviggi et al., RBMOnline, 2009

  24. LH gene polymorphism in women with ovarian resistance to FSH Overall incidence: 8/60 (13.3%) ‘Normal responders’: 0/22 (0%) ‘Ovarian resistance’: 8/22 (36.4%) Alviggi et al., RBMOnline, 2009

  25. Association between a point mutation of native LH and different profiles of ovarian response to rFSH Alviggi et al., Hum Reprod - Supp.1 2009 204normogonadotrophic patients undergoing a GnRH-a long protocol with rFSH prospectively collected and retrospectively analysed. IFMA assays were performed in each patient to find out the presence of v-LH Statistic model: one-way ANOVA with v-LH as independent variant

  26. RESULTS 24 [11.6 %] v-LH carriers found 21 [10.2 %] heterozygotes 3 [1.4%] homozygotes Group 0= wild tipe carriers Group 1= heterozygotes Group 2= homozygotes

  27. LH levels during spontaneous and stimulated cycles Role of LH during intermediate folliculogenesis Who requires LH supplementation? All patients? Advaced reproductive age? Hyporesponders? Pharmacogenomics? Antagonists?

  28. Kolibianakis EM et al., 2007 7 RCT’s (701 patients), among which 5 reported agonist and 2 antagonist cycles.

  29. Since intermediate follicular phase • (Expression of LH receptors in the granulosa) • Sustain of FSH-dependent granulosa activities, including aromatase induction and growth factors release (IGF-1, EGF etc…) • Optimization of steroidogenesis • Reduction of progesterone production (?) Paracrine activity LH during folliculogenesis • Since early follicular phase • Induction of androgens production in the theca cells Increase in follicular recruitment

  30. LH during folliculogenesis • Since early follicular phase • Induction of androgens production in the theca cells Increase in follicular recruitment Role of androgens during follicular recruitment Enhancement of follicular recruitment Hillier et al. Baillieres Clin Obstet Gynaecol 1997 Induction of the expression of the FSH receptor in granulosa cells Hickey et al. Biol Reprod 2005 Increase in the aromatase activity Hillier et al. Mol Cell Endocrinol

  31. RCT 146 women - GnRH-a long protocol 75 treated with rLH (300 IU) for 7 days rFSH 150 IU/day rLH 300 IU hCG DAYS 21 1 2 3 4 5 6 7 S1 S2 S3 S4… GnRH – a depot

  32. rFSH 150 IU/day rLH 300 IU hCG DAYS 21 1 2 3 4 5 6 7 S1 S2 S3 S4… GnRH – a depot

  33. r-LH 300 IU RCT 114 women – GnRH-a short protocol 58 treated with hCG (200 IU) for 7gg 56 treated with rLH (300 IU) for 7days rFSH 200 IU/day hCG 200 IU hCG DAYS 21 1 2 3 4 5 6 7 S1 S2 S3 S4… GnRH – a daily

  34. LH during folliculogenesis • Since early follicular phase • Induction of androgens production in the theca cells Increase in follicular recruitment Use of LH for androgens induction Conclusions Several studies demonstrate an effect of LH or hCG priming on follicle recruitment Higher dosages of r-hLH should be tested in these patients

  35. Use of r-hLH in IVF/ICSI CyclesCONCLUSION • RCTs and one meta-analysis have demonstrated that recombinant LH (r-hLH) supplementation does not improve neither ovarian response nor IVF outcome in patients treated with GnRH-analogues • There is evidence (RCTs and one meta-analysis) that women with ‘ovarian resistance’ (hypo-response) to rFSH benefit from rLH supplementation (irrespective of basal and post-GnRH-a LH levels) Common LH polymorphism is associated with hypo-response: pharmacogenetic bases for personalizing controlled OS protocols (higher FSH doses - LH supplementation) • Small evidence (1 RCT and two retrospective studies) suggesting that rLH improves outcome of IVF in women >35 years • The role of rLH priming before FSH and in modulating Progesterone rise during COS should be defined

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