LH activity for Gonadotrphin in controlled ovarian hyperstimulation : LH or just FSH?

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…