What gonadotropin physiology can teach us to improve ovarian stimulation
Stephen G. Hillier
MRC Centre for Reproductive Health The University of Edinburgh
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 stimul us f or 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 stimul us f or 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.
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