LH - hCG effect in human assisted fertility

Peter Platteau, MD FRCOG Centre for Reproductive Medicine Vrije Universiteit Brussel Brussels, Belgium

t 40 hr

t 20 min

Carboxy terminal peptide

LH Versus hCG: Overview

LH and hCG are structurally similar1 They bind to and activate the same receptor1 Compared with LH, hCG has25:
68 times longer half-life Greater stability

hCG, human chorionic gonadotrophin; LH, luteinising hormone.

1. Dufau. Annu Rev Physiol. 1998;60:461496. 2. Ross. Am J Obstet Gynecol. 1977;129 (7):795808. 3. Damewood et al. Fertil Steril. 1989;52(3):398400.

4. 5.

Yen et al. J Clin Endocrinol Metab. 1968;28 (12):17631767. Stokman et al. Fertil Steril .1993;60(1):175178.

Differences in LH-activity Between hCG and LH

Serum LH-activity in hCG and LH

Serum LH-activity

hCG
LH
Time Administration 24 Hours

Half life of hCG is 6-8 times longer than LH 1,2 hCG is six times more potent than LH1,2

hCG, human chorionic gonadotrophin; LH, luteinising hormone.

1. Stokman et al. Fertil Steril. 1993;60(1):175178. 2. Filicori et al. Hum Reprod Update. 2002;8(6):543557.

Follicular cells and hormones

HCG
Cholesterol

Theca

Granulosa

FSH
Cholesterol

Progesterone

Progesterone

Androgens

Androgens

Estrogens
9

Two sources of progesterone one step of further metabolism

LH and hCG content in different commercial gonadotrophin drug products1

MENOPUR LH (IU/L) hCG (IU/L)

PERGONAL

HUMEGON

GONAL-F

0.4 9.9

13.5 3.4

5.8 6.9

10

1. Wolfenson et al. Reprod Biomed Online 2005; 10 (4): 442454

MERiT Study protocol1

Triptorelin 0.1 mg daily SC
MENOPUR SC or GONAL-F SC

rhCG 250 g SC
Oocyte/ embryo evaluation FF B

Progesterone 90 mg daily vaginally

225 IU x 5 days
Adjustment by 75 IU Min 4 days on dose B

-hCG

TVU

TVU

1
57 days prior to menses Confirmation of downregulation

OR
3 follicles 17mm

ET

2 56 1011 Weeks after ET

Day 3 362 h 12 embryos

11 1.Andersen et al. Hum Reprod 2006; 21 (12): 32173227

Endocrine Profile
Higher With: HP-hMG
1.5

rFSH

Estradiol

1.5

Progesterone

0.5 Day 1
1.5

0.5

Day 6

hCG

OR

Day 1

Day 6

hCG

OR

Androstenedione

0.5 Day 1 Day 6 hCG OR

Ovulation Induction Cycles

Anovulation

MENOPUR OI : study flow1

HP-hMG (MENOPUR) sc, or rFSH (GONAL-F) sc 75 IU Dose kept or by 37.5 IU

hCG 5000 IU

Serum P4
hCG TVU TVU

X
Screening

X
Pregnancy monitoring

8
A dose level maintained for 7 days

69 days after hCG

1 follicle 17mm, or 23 follicles 15mm

25 days after start of menses

Follicles 10 mm: dose maintained No follicles 10 mm: dose increased

Pregnancy follow-up

1. Platteau et al. Hum Reprod 2006. Advance Access. Published 29 March 2006

Ovulation rate1
Non-inferiority limit
Ovulation rate
MENOPUR GONAL-F 86% (71/83) 85% (79/93) Difference [95% CI] 0.2 [-11.0; 11.3] -1.4 [-12.0; 9.1]

PP ITT

86% (60/70) 84% (76/91)

20 %

0 10 % 10 % Difference in ovulation rate GONAL-F better MENOPUR better

1. Platteau et al. Hum Reprod 2006. Advance Access. Published 29 March 2006

Pregnancy and live birth rate per cycle1

MENOPUR N=91 Clinical pregnancy 14 (15.4%) GONAL-F N=93 17 (18.3%)

Ongoing pregnancy
Singleton live birth

13 (14.3%)
13 (14.3%)

16 (17.2%)
14 (15.1%)

1. Platteau et al. Hum Reprod 2006. Advance Access. Published 29 March 2006

Complications1
MENOPUR N=91 OHSS, total OHSS risk or cycle cancellation due to excessive response Multiple pregnancy rate 1 (1%) 2% GONAL-F N=93 3 (3%) 10%

2 (2%)

1. Platteau et al. Hum Reprod 2006. Advance Access. Published 29 March 2006

Follicular development1
P=0.009
2

1.91

MENOPUR GONAL-F

NS
Follicles
1.24 1.04
1

NS
1.24

1.12

0.78

0
10 to 11 mm 12 to 16 mm > 17 mm

Follicles on day of hCG

1. Platteau et al. Hum Reprod 2006. Advance Access. Published 29 March 2006

IUI Cycles
Anovulation

A prospective randomized noninferiority study comparing recombinant FSH and highly purified menotropin in intrauterine insemination cycles in couples with unexplained infertility and/or mild-moderate male factor

Francesca Sagnella, M.D., Francesca Moro, M.D., Antonio Lanzone, M.D., Anna Tropea, M.D., Daniela Martinez, M.D., Antonio Capalbo, B.S., Maria Francesca Gangale, M.D., Valentina Spadoni, M.D., Andrea Morciano, M.D. and Rosanna Apa, M.D.

Fertility and Sterility Volume 95, Issue 2, Pages 689-694 (February 2011)
DOI: 10.1016/j.fertnstert.2010.08.044

Copyright 2011 American Society for Reproductive Medicine Terms and Conditions

Results
MENOPUR N=261 Clinical pregnancy 19.7 % GONAL-F N=262 21.4 %

Total dose (IU)

Days of stimulation Intermediate Follicles Follicles > 17mm day hCG

672.12
7.08 0.73

742.79
7.27 1.96

1.27

1.69

Complications
MENOPUR N=261 cycle cancellation due to excessive response or OHSS risk Multiple pregnancy rate 1.2 % GONAL-F N=262 8.4 %

0.7 % (2)

1.5 % (4)

ICSI

A significantly better live birth rate with hMG versus rFSH

N
EISG 2002 Gordon 2001 Ng 2001 Westergaard 2001 MERiT 2006 727 68 40 379 731

hMG
23% 31% 20% 35% 27%

rFSH
21% 23% 20% 28% 22%

Odds ratio 95% CI 1.17 [0.82, 1.66] 1.50 [0.51, 4.41] 1.00 [0.22, 4.62] 1.42 [0.92, 2.18] 1.20 [0.93, 1.55] 1.09 [0.53, 2.24] 0.75 [0.30, 1.90] 1.18 [1.02, 1.38]

Kilani 2003 Balasch 2003

Pooled results for truly randomised trials

100 50

24% 20%
27%

22% 27%
23%

0.1

0.2

0.5

10

Increased with rFSH

Increased with hMG

Analysis of the pooled data showed a statistically significant (p=0.03) increase in live births with hMG versus rFSH1
1. Coomarasamy et al. Hum Reprod submitted

Significantly lower progesterone levels at the end of stimulation with HP-hMG versus rFSH1
Progesterone profile HP-hMG rFSH p value

(nmol/L)

(N=363)
1.4 0.6

(N=368)
1.5 0.7

Day 6 of stimulation

0.333

Day of hCG administration

2.6 1.3

3.4 1.7

<0.001

Day of oocyte retrieval

24.5 15.6

36.3 25.0

<0.001

Occurrence

1 in 8

1 in 4

1. Smitz et al. Hum Reprod 2007; 22: 676687

Normal follicular phase profile

20 Progesterone (nmol/L)

LH peak

15

10 Endometrial changes
and between what limits

4 2 0 Day relative to LH peak

+2

Owen. Am J Clin Nutr 1975; 28: 333338

Ongoing pregnancy rate by serum hCG on Day 6: HP-hMG1

HP-hMG Ongoing pregnancy hCG on Day 6 (IU/L)

0.01.5 (N=33)
1.52.0 (N=71)

15%
20%

2.02.5 (N=99)
2.53.0 (N=77) >3.0 (N=75)

25%
35% 32%

p=0.040

Top Quality Embryos by Serum hCG on Day 6: HP-hMG

HP-hMG Mean Number of Top Quality Embryos hCG on Day 6 (IU/L) 0 to 1.5 (n=33) 1.5 to 2.0 (n=71) 0.67 0.62

2.0 to 2.5 (n=99)

2.5 to 3.0 (n=77) >3.0 (n=75)

0.77
1.14 1.24

P=0.009

Ziebe S, et al. 21st ESHRE. June, 2005. Abstract i76 (O-205).

Schematic overview of daily hormone treatment for treatment groups in a RCT for women undergoing ICSI.

Blockeel C et al. Hum. Reprod. 2009;24:2910-2916

The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The Future : another dimension of stimulation

The Future : HCG / FSH Pen For OI to increase monofollicular growth For IUI to control the number of growing follicles For IVF to reduce the Progesteron levels and save the endometrium (esp in high responders) and get a better selection of follicles which increases the embryo quality