LH like activity is claimed to be of importance for COH in IVF/ ICSI cycles. is this real. Does addition of LH make GN more superior? this talk may answer this

1. Does the addition of LH-Does the addition of LH-
activity to FSH makeactivity to FSH make
gonadotrophins moregonadotrophins more
superior:superior:
a systematic review and meta-analysis
Hesham G. Al-Inany, M.D., Ph.D.

2. Background

3. Classification of gonadotrophins
• Source of gonadotrophins:
– Urinary vs. Recombinant gonadotrophins (Gn)
• Chemical composition:
– FSH only vs. FSH + LH-containing Gn
• Isoforms:
– Fixed isoforms (recFSH, recLH) vs. multiple
isoforms (HP-FSH, HP-hMG, hCG)
FSH: 8 main isoforms
LH: 12 main isoforms
hCG: 30 main isoforms

4. Previous systematic reviews
• Primarily focused on sources of Gn
• Urinary hMG vs. Recombinant FSH
– Higher pregnancy and live-birth rates with hMG
– No difference in OHSS rates
Al-Inany et al., 2008; Coomarasamy et al., 2008Al-Inany et al., 2008; Coomarasamy et al., 2008
• Urinary HP-FSH vs. Recombinant FSH
– Similar pregnancy and live-birth rates
– No difference in OHSS rates
Al-Inany et al., 2011; Moustafa et al., 2009Al-Inany et al., 2011; Moustafa et al., 2009

5. Objective
To systematically locatesystematically locate, reviewreview and
analyzeanalyze the best available evidence for
the use of gonadotrophins according to
their chemical compositionchemical composition rather
than their sourcesource

6. Methods

7. • Computerized search:
– MEDLINE (1978 to present)
– EMBASE (1980 to present)
– Cochrane Central Register of Controlled Trials (CENTRAL)
– Trial registries of controlled trials (e.g. www.controlled-trials.com)
• Hand search:
– Reference lists of all known primary studies
– Review articles
– Citation lists of relevant publications
– Abstracts of major scientific meetings
Search strategy

8. Inclusion Criteria: PICOTS
• Population:
Randomized women undergoing IVF/ ICSI
• Intervention/ Control:
- Arm 1: FSH only (recFSH)
- Arm 2: FSH + LH-activity
(recFSH + recLH or hMG)
• Timing:
- FSH + LH concomitantly
- FSH then FSH + LH

9. Inclusion Criteria: PICOTS
• Outcomes:
- Primary outcomes:
- Live-birth rate
- OHSS rate
- Secondary outcomes:
- Ongoing pregnancy rate
- Clinical pregnancy rate
- Cycle characteristics

10. Exclusion criteria
• Non-randomized trials
• Trials using LH priming
- LH only then FSH only
• Trials using HP-FSH instead of recFSH
- not pure FSH
- contains some LH

11. • For the meta-analysis, the number of
participants experiencing the event was
recorded
• Data was extracted to allow for an intention-
to-treat analysis
• Defined as including in the denominator all
randomized cycles
Meta-analysis - Dichotomous

12. • Meta-analysis was performed:
– Mantel-Haenszel method, utilizing a random-
effects model
– Odds ratio (OR) and 95% confidence
intervals (CI) evaluated
Meta-analysis - Dichotomous

13. • Meta-analysis was performed:
– Inverse variance method, utilizing a random-
effects model
– Mean difference (MD) and 95% confidence
intervals (CI) evaluated
– Standardized Mean Difference (SMD) used
when multiple scales provided (E2)
Meta-analysis - Continuous

14. Results

16. 31 RCTs
10 RCTs
recFSH vs.
recFSH + recLH
21 RCTs
recFSH
vs. hMG/ HP-hMG
Follow-up
9 OHSS9 LBR

17. Primary outcomes

18. Live-birth rates
recFSH (304/ 1120; 27.14%) vs. FSH/LH (324/ 1110; 29.19%)
(P = 0.29; O.R = 0.90, 95% CI = 0.75 to 1.09)

19. OHSS rates
recFSH (34/ 1888; 1.80%) vs. FSH/LH(29/ 1843; 1.57%)
(P = 0.79; O.R = 1.08, 95% CI = 0.63 to 1.83)

20. Secondary outcomes

21. Ongoingpregnancyrate
recFSH (544/ 2385; 22.81%) vs. FSH/LH (589/ 2363; 24.93%)
(P = 0.31; O.R = 0.93, 95% CI = 0.81 to 1.07)

22. Clinicalpregnancyrates

23. Cycle characteristics

24. No. of oocytes retrieved
recFSH vs. FSH/LH
(P = 0.002; M.D = 1.25, 95% CI = 0.48 to 2.02)

25. Other cycle characteristics
• Treatment duration
• Amount of FSH
• Estradiol on day of hCG
• Progesterone on day of hCG
• Rate of poor responders
NSNS

26. Interpretation

27. Interpretation
• LH activity during ovulation induction
is not paramount
• Live-birth and OHSS rates were not
significantly different with LH-
containing protocols
• CPR significantly favored additional
LH-activity while number of oocytes
were higher with FSH-only protocols

28. Questioning LH-activity
• Subgroup analysis of CPR showed a
significant difference in favor of hMG
but not recFSH + recLH
• Therefore LH-activity per se may not
be the underlying source driving this
significant difference
• Multiple isoforms found in hMG/ HP-
hMG or larger sample size for CPR
may be a factor (Type II error)

29. Possible explanations
• Multiple gondotrophin isoforms in
hMG/ HP-hMG may provide better
coverage than a single isoform
• Glycosylated isoforms of FSH, LH and
hCG have been shown to be important
for the biological activities of these
hormones that allow for pleiotropic
signals to be transduced effectively at
the receptor-level Arey et al., 2011Arey et al., 2011

30. Future research
• HP-hMG vs. HP-FSH
‾ Distinguish importance between
LH-activity or multiple isoforms
• recFSH + recLH in subgroups:
‾ Poor responders
‾ Advanced maternal age

31. Thank You…