lh activity for gonadotrphin in controlled ovarian hyperstimulation : lh or just fsh?
DESCRIPTION
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 thisTRANSCRIPT
Does the addition of LH-Does the addition of LH-activity to FSH make activity to FSH make gonadotrophins more gonadotrophins more
superior:superior:a systematic review and meta-analysis
Hesham G. Al-Inany, M.D., Ph.D.
Background
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 isoformsLH: 12 main isoforms
hCG: 30 main isoforms
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
ObjectiveTo systematically locatesystematically locate, reviewreview and analyzeanalyze the best available evidence for the use of gonadotrophins according to their chemical composition chemical composition rather than their sourcesource
Methods
• 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
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
Inclusion Criteria: PICOTS• Outcomes:
- Primary outcomes:- Live-birth rate- OHSS rate
- Secondary outcomes:- Ongoing pregnancy rate- Clinical pregnancy rate
- Cycle characteristics
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
• 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
• Meta-analysis was performed:– Mantel-Haenszel method, utilizing a random-
effects model– Odds ratio (OR) and 95% confidence
intervals (CI) evaluated
Meta-analysis - Dichotomous
• 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
Results
31 RCTs
10 RCTs recFSH vs.
recFSH + recLH
21 RCTs recFSH
vs. hMG/ HP-hMG
Follow-up
9 OHSS9 LBR
Primary outcomes
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)
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)
Secondary outcomes
Ong
oing
pre
gnan
cy ra
te
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)
Clin
ical
pre
gnan
cy ra
tes
Cycle characteristics
No. of oocytes retrieved
recFSH vs. FSH/LH(P = 0.002; M.D = 1.25, 95% CI = 0.48 to 2.02)
Other cycle characteristics
• Treatment duration• Amount of FSH• Estradiol on day of hCG• Progesterone on day of hCG• Rate of poor responders
NSNS
Interpretation
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
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)
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
Future research• HP-hMG vs. HP-FSH
‾ Distinguish importance between LH-activity or multiple isoforms
• recFSH + recLH in subgroups:‾ Poor responders‾ Advanced maternal age
Thank You…