title: Recombinant LH supplementation to a standard GnRH antagonist protocol in women of 35 years or older undergoing IVF/ICSI: a randomized controlled multicentre study.
abstract: OBJECTIVE
  Does the addition of exogenous LH to an IVF/ICSI stimulation protocol with recombinant FSH (r-FSH) and a GnRH antagonist improve the ovarian response and pregnancy rates in women of 35 years and older?
  
  
  CONCLUSIONS
  Supplementation of LH during the second half of the follicular phase has no effect on pregnancy rates, implantation rates or on ovarian response in women of 35 years and older undergoing GnRH antagonist IVF/ICSI cycles.
  
  
  BACKGROUND
  In IVF/ICSI stimulation protocols GnRH agonists or antagonists are administered to prevent a premature pituitary LH surge, which can have a detrimental effect on the IVF/ICSI procedure. In effect, GnRH analogues cause the levels of both gonadotrophins to drop. In order to allow follicle growth FSH is administered exogenously, whereas LH is usually not supplemented. Although GnRH analogues prevent LH surges, there is evidence that, particularly in older women, administration of GnRH analogues may cause endogenous LH levels to decrease excessively. Several studies have been performed to investigate whether the addition of recombinant LH (r-LH) to r-FSH improves cycle outcome. Only a few studies have analysed this issue in the GnRH antagonist protocol and the results of these trials obtained in older women (>35 years old) are conflicting.
  
  
  METHODS
  A multicentre RCT was performed between 2004 and 2010 in 253 couples who were undergoing IVF or ICSI. Women were 35 years or older and received ovarian stimulation in a protocol with r-FSH (Gonal-F 225 IU/day) starting from cycle day 3 and GnRH antagonist (Cetrotide 0.25 mg/day) from stimulation day 6. Randomization took place on stimulation day 6 to receive both r-FSH and r-LH (Luveris 150 IU/day) or continue with FSH alone. Randomization for r-LH supplementation was performed centrally by serially numbered, opaque, sealed envelopes, stratified by centre.
  
  
  METHODS
  Of 253 subjects randomized, 125 received both r-FSH and r-LH and 128 received r-FSH only. Patients were recruited from the Division of Reproductive Medicine of the Obstetrics and Gynaecology department of four hospitals in the Netherlands.
  
  
  RESULTS
  There were no demographic or clinical differences between the groups. The intention-to-treat analysis revealed that of those receiving both r-FSH and r-LH, 35 (28.0%) had a clinical pregnancy, compared with 38 (29.7%) receiving only r-FSH (mean difference -1.5%; 95% confidence interval (CI) -9.4 to 12.7, P = 0.9). Ongoing pregnancy rates were 25 (20%) versus 28 (21.9%) (mean difference -1.9%; 95% CI -8.2 to 11.9, P = 0.9) and implantation rates 18.8 versus 20.7% (mean difference -1.9%; 95% CI -8.0 to 11.7, P = 0.6) in the 'r-FSH and r-LH' and 'r-FSH only' groups respectively.
  
  
  CONCLUSIONS
  A limitation of our study is its early closure. This was done because the interim analysis after randomization of 250 patients indicated no benefit in any aspect of the experiment.
  
  
  CONCLUSIONS
  Given previous data, including a Cochrane review, and our own results the evidence indicates that LH supplementation has no benefit on ongoing pregnancy rates in women of 35 years or older.
  
  
  BACKGROUND
  Merck Serono Netherlands, an affiliate of Merck Serono SA- Geneva, an affiliate of Merck KGaA, Darmstadt, Germany has donated the r-LH (Luveris(®)). No conflict of interest to declare.
  
  
  BACKGROUND
  The trial was registered in the Dutch trial register (ISRCTN10841210).
authors.affiliation: Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, VU University Medical Center (VUmc), PO Box 7057, Amsterdam 1007 MB, The Netherlands.
authors.forename: T E
authors.initials: TE
authors.lastname: König
authors.forename: L E E
authors.initials: LE
authors.lastname: van der Houwen
authors.forename: A
authors.initials: A
authors.lastname: Overbeek
authors.forename: M L
authors.initials: ML
authors.lastname: Hendriks
authors.forename: S N
authors.initials: SN
authors.lastname: Beutler-Beemsterboer
authors.forename: W K H
authors.initials: WK
authors.lastname: Kuchenbecker
authors.forename: C N M
authors.initials: CN
authors.lastname: Renckens
authors.forename: R E
authors.initials: RE
authors.lastname: Bernardus
authors.forename: R
authors.initials: R
authors.lastname: Schats
authors.forename: R
authors.initials: R
authors.lastname: Homburg
authors.forename: P G A
authors.initials: PG
authors.lastname: Hompes
authors.forename: C B
authors.initials: CB
authors.lastname: Lambalk
mesh_terms: D000328:Adult; D005260:Female; D005307:Fertilization in Vitro / Q000379:methods*; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D016015:Logistic Models; D007986:Luteinizing Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D010062:Ovulation Induction / Q000379:methods; D011247:Pregnancy; D018873:Pregnancy Rate
chemical_list: D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; C062876:cetrorelix
keywords: GnRH antagonist; LH; assisted reproduction technology; ovarian stimulation; pregnancy rates