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.

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. Greetings from Craft Kodungallur & Chennai

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. LH has a multifaceted role in reproductive cycle

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. There is no optimal LH level to aim for during COS

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. 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. Micah J. Hill et al, The Use of rLH, HMG and hCG in COS for ART,2012

10. No role of LHS in unselected population

11. rLH + rFSH vs rFSH
Meta-analysis of long agonist protocol
RCTs

12. LHS is thought to be useful in certain subgroups

14. LH is mandatory in COS of hypo hypo women

15. No increase in E2 with
rFSH alone
Good increase in E2
with rFSH + rLH
Shoham et al,fertil steril,1993

16. The European Recombinant Human LH study Group,JCEM, 1998

17. 75 IU LH is sufficient in majority

18. More evidence is needed for indispensability of LH in POR

19. Cochrane review
LHS is beneficial in poor responders
Mochtar et al,2010

20. • Studies: 3 trials,458 patients
• Primary outcome: OPR at 12weeks
Ongoing pregnancy rate:No significant improvement

21. LH addition is beneficial in women with slow response to FSH

22. Human Reproduction,2005
65
Step up rFSH 150 IU
65
+ rLH 150 IU
130
260 women on 225 IU rFSH
Inadequate response
130 Normoresponder

23. LHS may be benefit women with advanced age

24. 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.

25. 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

26. Ongoing pregnancy rate per started cycle : OR 1.49; 95% CI 0.93–2.38; P=09
Bosch et al,Fertil steril,2011

27. No definite evidence of benefit of LHS in women with low LH levels

28. How low is too low?
Don’t know!!

29. 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

30. 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

31. No conclusive evidence to suggest detrimental effect of
low LH levels in long agonist protocol

32. Human reproduction,2003
• 246 women
• Study point : LH levels on day of DR,day 5 ,and so on

33. No difference

34. • 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

35. 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

36. Low LH levels in antagonist protocol are not detrimental to cycle outcome

37. • 116 women,rFSH 200 IU,Fixed antagonist from day 6
Kolibianakis EM et al, Hum Reprod Update 2007

38. 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.

39. No conclusive evidence to suggest a beneficial role of LH priming

40. 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.

41. •
•
•
•
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

42. Durnerin et al,human reproduction,2008

43. 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

44. No LH priming
LH priming
P

45. Which preparation to give?
•
•
•
•
rLH
HMG
hCG
Pergoveris
No conclusive evidence yet for choosing one over the other

46. 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

47. 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