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Role of LH supplementation in IVF

Dr Sankalp Singh
MS,DNB,MRCOG
Consultant in reproductive medicine
Craft hospital & rese...
Greetings from Craft Kodungallur & Chennai
Focus of the talk
• Physiological role of LH in reproduction
• To know whether an ‘optimal LH level’ exist
• Which patient...
LH has a multifaceted role in reproductive cycle
Multifaceted role of LH
Endometrial effects

premature P4 rise

Estradiol

Modified from Micah J. Hill et al, The Use of r...
There is no optimal LH level to aim for during COS
Subdivisions of LH levels
Ceiling1

Window

Threshold2

• Selective/complete
follicular growth
arrest
• Premature
Luteiniz...
Few facts..
• Commercial immunoassays are much reliable to detect higher ceiling
levels rather than low levels.
• Analytic...
Micah J. Hill et al, The Use of rLH, HMG and hCG in COS for ART,2012
No role of LHS in unselected population
rLH + rFSH vs rFSH
Meta-analysis of long agonist protocol

RCTs
LHS is thought to be useful in certain subgroups
LH is mandatory in COS of hypo hypo women
No increase in E2 with
rFSH alone

Good increase in E2
with rFSH + rLH
Shoham et al,fertil steril,1993
The European Recombinant Human LH study Group,JCEM, 1998
75 IU LH is sufficient in majority
More evidence is needed for indispensability of LH in POR
Cochrane review

LHS is beneficial in poor responders
Mochtar et al,2010
• Studies: 3 trials,458 patients
• Primary outcome: OPR at 12weeks
Ongoing pregnancy rate:No significant improvement
LH addition is beneficial in women with slow response to FSH
Human Reproduction,2005

65

Step up rFSH 150 IU

65

+ rLH 150 IU

130
260 women on 225 IU rFSH

Inadequate response

130...
LHS may be benefit women with advanced age
Proposed theories for LH need in advanced age
Reduced functional LH
receptors 1

Reduced androgen
production 2

Advanced a...
Meta-analysis for LHS in advanced age
• 7 trials,902 ART cycles
• CPR:

• Conclusion :addition of recombinant LH to this s...
Ongoing pregnancy rate per started cycle : OR 1.49; 95% CI 0.93–2.38; P=09

Bosch et al,Fertil steril,2011
No definite evidence of benefit of LHS in women with low LH levels
How low is too low?

Don’t know!!
Search for LH threshold – observational studies
Authors
measure

day LH

LH threshold

assessed

used

day 7-9

0.5 IU/L

...
Why no consensus yet for the optimal LH level?

LH

patient selection criteria

Varying clinical end-points
Differing seru...
No conclusive evidence to suggest detrimental effect of
low LH levels in long agonist protocol
Human reproduction,2003

• 246 women
• Study point : LH levels on day of DR,day 5 ,and so on
No difference
• Studies: 6 studies,1103 patients
• Primary outcome: ongoing pregnancy rate at 12weeks

• Conclusion : low endogenous LH ...
Reason why LH might not be needed in long
agonist protocol
• In normogonadotrophic, vis a vis hypo hypo, normal LH
levels ...
Low LH levels in antagonist protocol are not detrimental to cycle outcome
• 116 women,rFSH 200 IU,Fixed antagonist from day 6

Kolibianakis EM et al, Hum Reprod Update 2007
Endogenous LH Levels in GnRH Antagonist Protocol
(ENGAGE trial)
• Retrospective analysis

• 750 pts
• rFSH only

No differ...
No conclusive evidence to suggest a beneficial role of LH priming
Basis of LH priming
• LH receptors can be found on theca cells of follicles
at preantral and antral stages
• By increasing...
•
•
•
•

Study design: RCT,
Ovarian stimulation: GnRH agonist long depot protocol rFSH 150 IU.
Intervention : rLH 300 IU f...
Durnerin et al,human reproduction,2008
No LH priming
Long agonist

n=75
Day 1

2

3

4

5

6

7

8

9

10

rFSH 150 IU

LH priming group
Long agonist

n=75
Day 1...
No LH priming

LH priming

P
Which preparation to give?
•
•
•
•

rLH
HMG
hCG
Pergoveris

No conclusive evidence yet for choosing one over the other
Gynaecol endocrinol 2011

• Study design : Observational matched case control of 4719 women
• Intervention : rLH+rFSH(1:2)...
LH Supplementation : Summary and conclusion
• No definite known LH threshold below which IVF outcome is
compromised
• LH s...
Role of LH supplementation in reproductive medicine - Aspire 2013
Role of LH supplementation in reproductive medicine - Aspire 2013
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Role of LH supplementation in reproductive medicine - Aspire 2013

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To add or not to add LH is a highly contentious issue.Here,i would be discussing role of LH supplementation in IVF cycle as per present day evidence.
Also,will be scrutinising the available studies for their reliability or lack of it.

Published in: Health & Medicine
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Role of LH supplementation in reproductive medicine - Aspire 2013

  1. 1. Role of LH supplementation in IVF Dr Sankalp Singh MS,DNB,MRCOG Consultant in reproductive medicine Craft hospital & research centre Kodungallur Aspire 2013
  2. 2. Greetings from Craft Kodungallur & Chennai
  3. 3. Focus of the talk • Physiological role of LH in reproduction • To know whether an ‘optimal LH level’ exist • Which patient population needs LH? • How to supplement LH?
  4. 4. LH has a multifaceted role in reproductive cycle
  5. 5. Multifaceted role of LH Endometrial effects premature P4 rise Estradiol Modified from Micah J. Hill et al, The Use of rLH, HMG and hCG in COS for ART,2012
  6. 6. There is no optimal LH level to aim for during COS
  7. 7. Subdivisions of LH levels Ceiling1 Window Threshold2 • Selective/complete follicular growth arrest • Premature Luteinization. • Compromised oocyte • Normal follicular development. • Adequate granulosa proliferation • Normal Androgen & Estrogen synthesis. • Good oocyte quality • ? Follicular growth impairement • ? Inadequate androgens and estrogens • ? Compromised oocyte 1-Hillier et al,Human reproduction,2003 2-Fleming et al,1996 Odea et al,2008
  8. 8. Few facts.. • Commercial immunoassays are much reliable to detect higher ceiling levels rather than low levels. • Analytical error and moment-to moment biological variation • No reliable way to differentiate b/w bioactive vs immunoactive LH. • Androgen synthesis and release are optimal even if only 1% receptors of LH are occupied.(Spare receptor hypothesis) Chappel et al,Human Reproduction. 1991 • Sudden change in LH level is more important than a single value. Huirne et al,Human reproduction 2005
  9. 9. Micah J. Hill et al, The Use of rLH, HMG and hCG in COS for ART,2012
  10. 10. No role of LHS in unselected population
  11. 11. rLH + rFSH vs rFSH Meta-analysis of long agonist protocol RCTs
  12. 12. LHS is thought to be useful in certain subgroups
  13. 13. LH is mandatory in COS of hypo hypo women
  14. 14. No increase in E2 with rFSH alone Good increase in E2 with rFSH + rLH Shoham et al,fertil steril,1993
  15. 15. The European Recombinant Human LH study Group,JCEM, 1998
  16. 16. 75 IU LH is sufficient in majority
  17. 17. More evidence is needed for indispensability of LH in POR
  18. 18. Cochrane review LHS is beneficial in poor responders Mochtar et al,2010
  19. 19. • Studies: 3 trials,458 patients • Primary outcome: OPR at 12weeks Ongoing pregnancy rate:No significant improvement
  20. 20. LH addition is beneficial in women with slow response to FSH
  21. 21. Human Reproduction,2005 65 Step up rFSH 150 IU 65 + rLH 150 IU 130 260 women on 225 IU rFSH Inadequate response 130 Normoresponder
  22. 22. LHS may be benefit women with advanced age
  23. 23. Proposed theories for LH need in advanced age Reduced functional LH receptors 1 Reduced androgen production 2 Advanced age Reduced bioactive LH 3 Reduced intraovarian paracrine activity 1 -Vihko et al,Eur J Endocrinol. 1996 Mar;134(3):357-61. 2 -Piltonen et al, J Clin Endocrinol Metab. 2003 Jul;88(7):3327-32. 3 -Warner et al, J Clin Endocrinol Metab. 1985 Feb;60(2):263-8.
  24. 24. Meta-analysis for LHS in advanced age • 7 trials,902 ART cycles • CPR: • Conclusion :addition of recombinant LH to this subgroup may improve implantation and clinical pregnancy. Hill et al,Fertil Steril,2012
  25. 25. Ongoing pregnancy rate per started cycle : OR 1.49; 95% CI 0.93–2.38; P=09 Bosch et al,Fertil steril,2011
  26. 26. No definite evidence of benefit of LHS in women with low LH levels
  27. 27. How low is too low? Don’t know!!
  28. 28. Search for LH threshold – observational studies Authors measure day LH LH threshold assessed used day 7-9 0.5 IU/L day 8 0.5 IU/L group Fleming et al, 1998 (retrospective) Westergaard et al, 2000 (retrospective) Balasch day 7 0.5, 0.7,1.0 IU/L day 5-12 et al, 2002 (retrospective) No significant difference In ovarian response and clinical outcome 3.0 IU/L et al, 2001 (retrospective) Humaidan in low LH Lower E2, oocytes retrieved, fertilization rate (NS) Lower E2 Higher early pregnancy loss (45% vs 9%, P <0.005) Significantly higher IR et al, 2001 (retrospective) Esposito outcome day 8 < 0.5 0.5 -1.0 1.01-1.5 > 1.5 Higher fertilization and clinical pregnancy in the group 0.5-1.5
  29. 29. Why no consensus yet for the optimal LH level? LH patient selection criteria Varying clinical end-points Differing serum LH assays Arbitrary LH cut-off values
  30. 30. No conclusive evidence to suggest detrimental effect of low LH levels in long agonist protocol
  31. 31. Human reproduction,2003 • 246 women • Study point : LH levels on day of DR,day 5 ,and so on
  32. 32. No difference
  33. 33. • Studies: 6 studies,1103 patients • Primary outcome: ongoing pregnancy rate at 12weeks • Conclusion : low endogenous LH levels are not associated with a significantly decreased probability of ongoing pregnancy beyond 12 weeks Kolibianakis EM et al, Hum Reprod Update 2007
  34. 34. Reason why LH might not be needed in long agonist protocol • In normogonadotrophic, vis a vis hypo hypo, normal LH levels prior to downregulation is able to ‘prime’ small follicles making them less sensitive to later LH drop. • Supraphysiological FSH may balance the lack of LH by inducing compensatory paracrine activities in GCs. • Spare receptor hypothesis
  35. 35. Low LH levels in antagonist protocol are not detrimental to cycle outcome
  36. 36. • 116 women,rFSH 200 IU,Fixed antagonist from day 6 Kolibianakis EM et al, Hum Reprod Update 2007
  37. 37. Endogenous LH Levels in GnRH Antagonist Protocol (ENGAGE trial) • Retrospective analysis • 750 pts • rFSH only No difference in Ongoing PR even with LH below 10th centile Doody KJ et al. Reprod Biomed Online. 2011.
  38. 38. No conclusive evidence to suggest a beneficial role of LH priming
  39. 39. Basis of LH priming • LH receptors can be found on theca cells of follicles at preantral and antral stages • By increasing androgens,LH priming can increase FSH sensitivity.
  40. 40. • • • • Study design: RCT, Ovarian stimulation: GnRH agonist long depot protocol rFSH 150 IU. Intervention : rLH 300 IU for 7 days before rFSH vs no rLH Primary outcome: follicular development No difference seen Durnerin et al,human reproduction,2008
  41. 41. Durnerin et al,human reproduction,2008
  42. 42. No LH priming Long agonist n=75 Day 1 2 3 4 5 6 7 8 9 10 rFSH 150 IU LH priming group Long agonist n=75 Day 1 2 3 4 5 6 7 LH 75 IU rFSH 150 IU 8 9 10
  43. 43. No LH priming LH priming P
  44. 44. Which preparation to give? • • • • rLH HMG hCG Pergoveris No conclusive evidence yet for choosing one over the other
  45. 45. Gynaecol endocrinol 2011 • Study design : Observational matched case control of 4719 women • Intervention : rLH+rFSH(1:2) vs uHMG+rFSH vs uHMG • Data : Recdate database in Germany,maintained by Merck Serono • Reasoning: • Longer half life and higher affinity of hCG may downregulate LH/hCG receptor mRNA making it unavailable for cellular action for upto 48 hrs Menon et al,Biol Reprod,2004 • Lower expression of genes of LH/hCG receptor and of Steroid Grohndahl et al,Fertil steril,2009 biosynthesis in HMG group
  46. 46. LH Supplementation : Summary and conclusion • No definite known LH threshold below which IVF outcome is compromised • LH supplementation is not indicated in unselected population/hyperresponders/normoresponders • Exogenous LH should be added in hypogonadotropic women. • Should be supplemented in suboptimal responders to rFSH in index cycle • More good quality evidence needed to recommend in known poor responders/Low LH levels. • Though promising, more robust data is needed in advanced age • Dose of 75 IU rLH/HMG is sufficient for most scenariosin promoting optimum follicular development. • Till further evidence, rLH=HMG=hCG

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