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 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 •TGF1, TGF2, TGF3 • Anti-Müllerian Hormone (AMH) • Inhibins, activins • Bone morphogenetic 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 (), GDF-9 • Nodal • Chicken dorsalin-1 (dsl-1) • Xenopus vegetal hemisphere Vg1, • Drosophila 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) () • 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 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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