What gonadotropin physiology can teach us to improve ovarian stimulation Stephen G . Hillier MRC Centre for Reproductive Health The University of Edinburgh [email protected] The follicle life-cycle LH FSH 20 2 Diameter (mm) Diameter .2 0044881212 Time (weeks) Superovulation Strategy 1. Increase the no. of ‘precursor’ follicles FSH 2. Raise the LH stimu lus for 25 preovulatory 20 1 growth 15 10 3. Override the 5 ‘selection’ Follicular(mm) diam 0 process 0 14 28 Day of menstrual cycle Hillier et al. 1985 Variable link between menstrual cycle onset and inter-cyclic FSH rise Onset of menses 9 8 7 6 5 (U/l) Average (mean±SD, n=8) Series1 H 4 FS Patient 1 3 Patient 2 2 1 0 ‐5 ‐4 ‐3 ‐2 ‐1 1234567891011142 3 5 6 Day of menstrual cycle The idea of an FSH ‘syncromesh’ Clomiphene hCG hFSH hMG 6 Patient: CW Age: 29 yr 4 Superovulation: hFSH dd 1-5 (nmol/l) 2 150 IU/d, 750 IU Clomiphene dd 5-9 0 100mg/d Oestradiol m 20 hMG dd 8-12 150 IU/d, 750 IU (mm) 16 Follicular dia 12 16 200 LH 8 100 (IU/l) hCG (IU/l) laparoscopy embryo replacement 0 0 13 57911131517 22 27 30 Day of cycle What gonadotropin physiology can teach us to improve ovarian stimulation • Paracrine ppyathways • Gonadotropic gearing • Clinical impact What gonadotropin physiology can teach us to improve ovarian stimulation • Paracrine ppyathways • Gonadotropic gearing • Clinical impact Age-related oocyte loss 11 yr 34 yr Stages of folliculogenesis PrimordialPrimary Secondary Tertiary Preovulatory FSH ? ? FSH LH AMH Paracrine pathways theca granulosa oocyte TGF superfamily •TGF1, TGF2, TGF3 • Anti-Müllerian Hormone (AMH) • Inhibins, activins • Bone morphogenetic proteins BMP-2, BMP-3 (osteogenin), BMP-3B (GDF- 10), BMP-4 (BMP-2B), BMP-5, BMP-6 (VGR-1), BMP-7 (OP-1), BMP-8 (OP-2), BMP-15 • Embryonic growth factor GDF-1, • Growth Differentiation Factors GDF-3, GDF-5, GDF-6, GDF-7, GDF-8 (myostatin), GDF-9 • Nodal • Chicken dorsalin-1 (dsl-1) • Xenopus vegetal hemisphere protein Vg1, • Drosophila decapentaplegic protein (DPP-C) • Drosophila protein screw (scw) • Drosophila protein 60A • Caenorhabditis elegans larval development regulatory growth factor daf-7 • Mammalian endometrial bleeding-associated factor (EBAF) (Lefty) • Mammalian glial cell line-derived neurotrophic factor (GDNF) Para(auto)crine cues AMH AMH AMH AMH AMH AMHAMH INHA INHA INHBB INHBA INHIBIN B INHIBIN A INHBA INHBB ACTIVIN Activin signalling PrimordialPrimary Secondary Tertiary AMH INHBA INHBB ACTIVIN A/B ` Fraser HM, Lunn SF, Whitelaw PF, Hillier SG. J Endocrinol. 1995 Activin signalling Miró & Hillier 1996 Primary Secondary Tertiary AMH INHBA INHBB ACTIVIN A/B Inhibin signalling Hillier et al 1991 Primary Secondary Tertiary AMH INHA INHBA INHIBIN A Paracrine pathways LH FSH LH LHR FSHR LHR Activin GDF9 Androgen Inhibin BMP15 theca granulosa oocyte Hillier S G Mol. Hum. Reprod. 2009;15:843-850 What gonadotropin physiology can teach us to improve ovarian stimulation • Paracrine ppyathways • Gonadotropic gearing • Clinical impact Gonadotropic gearing 1. Increase the no. of ‘precursor’ follicles FSH 2. Raise the LH stimu lus for 25 preovulatory 20 1 growth 15 10 3. Override the 5 ‘selection’ (mm)Follicular diam 0 process 0 14 28 Day of menstrual cycle Hillier et al. 1985 The follicle life-cycle: Recruitment LH FSH ovulation selection E recruitment 2 0 4 8 12 16 Day of cycle The follicular life-cycle: Recruitment LH LH FSH FSH ovulation theca granulosa selection E recruitment 2 0 4 8 12 16 Day of cycle The follicular life-cycle: Recruitment LH FSH ovulation selection E recruitment 2 Yong et al., JCEM 1993 0 4 8 12 16 Day of cycle FSH drives recruitment LH FSH The follicle life-cycle: Selection LH FSH ovulation selection E recruitment 2 0 4 8 12 16 Day of cycle LH drives selection LH LH FSH FSH LH ovulation theca granulosa selection E recruitment 2 0 4 8 12 16 Day of cycle FSH-like LH action LH FSH ovulation selection E recruitment 2 0 4 8 12 16 Day of cycle Development-related gonadotrophin action FSH on granulosa LH on granulosa LH on theca LH FSH -4 0 4 8 12 16 Day of cycle Paracrine pathways LH FSH LH LHR FSHR LHR Activin GDF9 Androgen Inhibin BMP15 theca granulosa oocyte Hillier S G Mol. Hum. Reprod. 2009;15:843-850 Paracrine pathways LH FSH LH LHR FSHR LHR Activin GDF9 Androgen Inhibin BMP15 theca granulosa oocyte Hillier S G Mol. Hum. Reprod. 2009;15:843-850 Androgens modulate FSH-induced gene expression in granulosa cells Tetsuka & Hillier ENDOCRINOLOGY 1996 What gonadotropin physiology can teach us to improve ovarian stimulation • Paracrine ppyathways • Gonadotropic gearing • Clinical impact Effects of recombinant LH treatment on folliculogenesis and responsiveness to FSH stimulation Durnerin CI, Erb K, Fleming R, Hillier H, Hillier SG, Howles CM, Hugues JN, Lass A, Lyall H, Rasmussen P, Thong J, Traynor I, Westergaard L, Yates R; Luveris Pretreatment Group. Hum Reprod. 2008 Feb;23(2):421-6. Group 1: No LH pre-treatment Group 2: LH pre-treatment LH FSH -8 -4 0 4 8 12 16 Day of cycle EvidenceEvidence that thatLH-priming LH priming can improve can oocyte improve quality. oocyte quality Durnerin CI, Erb K, Fleming R, Hillier H, Hillier SG, Howles CM, Hugues JN, Lass A, Lyall H, Rasmussen P, Thong J, Traynor I, Westergaard L, Yates R; Luveris Pretreatment Group. Hum Reprod. 2008 Feb;23(2):421-6. The use ofEvidence recombinant that LH priming can luteinizingimprove oocyte quality. hormone in patients undergoing assisted reproductive techniques with advanced reproductive age: a systematic review and meta-analysis. Forest plot of clinical pregnancy Fertil Steril. 2012 Feb 24. [Epub ahead of print] Hill MJ, Levens ED, Levy G, Ryan ME, Csokmay JM, Decherney AH, Whitcomb BW. Thank you!.