. 2021 Jun 21;19:91. doi: 10.1186/s12958-021-00759-4

Table 1.

Characteristics of studies included

Reference	Study type	Period of observation	Country	Pituitary suppression	Population	Intervention	Comparison	Results
Humaidan et al. 2004 [20]	RCT subgroup analysis	November 2001 to October 2002	Denmark (single-centre)	GnRH agonist long Buserelin 0.5 mg /day	N = 39 Age 35–40 years	Group A1 N = 21 r-hFSH +r-hLH r-hLH started at stimulation day 8 r-hLH dosage r-hFSH r-hLH ratio 2:1	Group B1 N = 18 r-hFSH	Significantly higher implantation rate in r-hLH supplemented group
Marrs et al. 2004 [19, 69]	RCT subgroup analysis	n.a	USA (multi-centre)	GnRH agonist long Leuprolide 0.5 mg/day	N = 121 Age 35–40 years	Group A N = 65 r-hFSH +r-hLH r-hLH started at stimulation day 6 r-hLH dosage 150 IU	Group B N = 56 r-hFSH	Higher implantation rate and clinical pregnancy rate in r-hLH supplemented group
Fabregues et al. 2006 [67]	RCT	November 2003 to September 2004	Spain (single-centre)	GnRH agonist long Triptorelin 0.1 mg/day	N = 120 Age 35–42 years	Group A N = 60 r-hFSH + r-hLH r-hLH started at stimulation day 6 r-hLH dosage 150 IU	Group B N = 60 r-hFSH	Significantly lower number of oocytes retrieved and MII oocytes in r-hLH supplemented group Comparable implantation rate and pregnancy rates between groups
Barrenetxea et al. 2008 [70]	RCT	January to June 2005	Spain (single-centre)	GnRH agonist short Leuprolide 0.5 mg	N = 84 Age ≥ 40 years	Group A N = 42 r-hFSH + r-hLH r-hLH started at stimulation day 7 r-hLH dosage 150 IU	Group B N = 42 r-hFSH	Comparable implantation rate, pregnancy rates and number of oocytes retrieved between groups
N. Andersen et al. 2008 [65]	RCT subgroup analysis	August 2003 to November 2004	Denmark Sweden Norway Finland (multi-centre)	GnRH agonist long Nafarelin 200 μg twice a day	N = 100 Age 35–40 years	Group A N = 49 r-hFSH +r-hLH r-hLH started at stimulation day 6 r-hLH dosage 150 IU	Group B N = 51 r-hFSH	Comparable clinical pregnancy rate, implantation rate and number of oocytes retrieved between groups
Matorras et al. 2009 [64]	RCT	January 2005 to November 2006	Spain (single-centre)	GnRH agonist long Triptorelin 0.1 mg/day	N = 131 Age 35–39 years	Group B N = 63 r-hFSH + r-hLH r-hLH started at stimulation day 6 r-hLH dosage 150 IU	Group A N = 68 r-hFSH	Significantly higher implantation rate, live birth rate in r-hLH supplemented group. Higher clinical pregnancy rate in r-hLH supplemented group
Bosch et al. 2011 [9]	RCT	January 2005 to December 2007	Spain (single-centre)	GnRH antagonist Cetrorelix 0.25 mg/day OC during the cycle before stimulation	N = 292 Age 36–39 years	Group A N = 150 r-hFSH + r-hLH r-hLH dosage 75 IU r-hLH started at stimulation day 1	Group B N = 142 r-hFSH	Significantly lower number of oocytes retrieved in r-hLH supplemented group Significantly higher implantation rate in r-hLH supplemented group Higher clinical pregnancy rates in r-hLH supplemented group
Fabregues et al. 2011 [68]	RCT	January 2007 to February 2008	Spain (single-centre)	GnRH agonist long Triptorelin 0.1 mg /day	N = 187 Age 35–41 years	Group A1 N = 62 r-hFSH + r-hLH Group A2 n = 63 r-hFSH + r-hLH r-hLH started at stimulation day 6 in A1 and A2 Group A1 r-hLH dosage 37.5 IU Group A2 r-hLH dosage 75 IU	Group B N = 62 r-hFSH	Significantly lower number of oocytes retrieved and MII oocytes in r-hLH supplemented group Comparable implantation rate and pregnancy rates between groups
Konig et al. 2013 [36]	RCT	January 2004 to September 2010	Netherlands (multi-centre)	GnRH antagonist Cetrorelix 0.25 mg/day	N = 253 Age 35–43 years	Group A N = 125 r-hFSH + r-hLH r-hLH started at stimulation day 6 r-hLH dosage 150 IU	Group B N = 128 r-hFSH	Comparable clinical pregnancy rate, implantation rate and n oocytes retrieved between groups
Vuong et al. 2015 [37]	RCT	October 2012 to June 2014	Vietnam (single-centre)	GnRH antagonist Cetrorelix	N = 240 Age ≥ 35 years	Group A N = 120 r-hFSH + r-hLH r-hLH started at stimulation day 6 r-hLH dosage 75 IU	Group B N = 120 r-hFSH	Comparable clinical pregnancy rate, implantation rate and number of oocytes retrieved between groups
Younis et al. 2016 [66]	RCT	April 2010 to April 2013	Israel (single-centre)	GnRH antagonist Cetrorelix 0.25 mg/day	N = 62 Age 35–44 years	Group A N = 32 r-hFSH +r-hLH r-hLH started with antagonist r-hLH dosage r-hFSH r-hLH ratio 2:1	Group B N = 30 r-hFSH	Comparable clinical pregnancy rate, implantation rate and number of oocytes retrieved between groups
Humaidan et al. 2017 [71]	RCT	January 2014 and February 2015	Denmark (multi-centre)	GnRH agonist long Triptorelin acetate 0.1 mg	N = 821 Age 35–41 years BMI 18–31 kg/m2 Poor response according the Bologna criteria	Group A N = 405 r-hFSH + r-hLH r-hLH started at stimulation day 1 r-hLH dosage r-hFSH r-hLH ratio 2:1	Group B N = 416 r-hFSH	Comparable number of oocytes retrieved

Reference

Study type

Period of observation

Country

Pituitary suppression

Population

Intervention

Comparison

Results

Humaidan et al. 2004 [20]

RCT subgroup analysis

November 2001 to October 2002

Denmark

(single-centre)

GnRH agonist

long

Buserelin

0.5 mg /day

N = 39

Age 35–40 years

Group A1

N = 21

r-hFSH +r-hLH

r-hLH started at stimulation day 8

r-hLH dosage

r-hFSH r-hLH ratio 2:1

Group B1

N = 18

r-hFSH

Significantly higher implantation rate in r-hLH supplemented group

Marrs et al. 2004 [19, 69]

RCT subgroup analysis

n.a

USA

(multi-centre)

GnRH agonist long

Leuprolide 0.5 mg/day

N = 121

Age 35–40 years

Group A

N = 65

r-hFSH +r-hLH

r-hLH started at stimulation day 6

r-hLH dosage

150 IU

Group B

N = 56

r-hFSH

Higher implantation rate and clinical pregnancy rate in r-hLH supplemented group

Fabregues et al. 2006 [67]

RCT

November 2003 to September 2004

Spain

(single-centre)

GnRH agonist

long

Triptorelin

0.1 mg/day

N = 120

Age 35–42 years

Group A

N = 60

r-hFSH + r-hLH

r-hLH started at stimulation day 6

r-hLH dosage

150 IU

Group B

N = 60

r-hFSH

Significantly lower number of oocytes retrieved and MII oocytes in r-hLH supplemented group

Comparable implantation rate and pregnancy rates between groups

Barrenetxea et al. 2008 [70]

RCT

January to June 2005

Spain

(single-centre)

GnRH agonist

short

Leuprolide

0.5 mg

N = 84

Age ≥ 40 years

Group A

N = 42

r-hFSH + r-hLH

r-hLH started at stimulation day 7

r-hLH dosage

150 IU

Group B

N = 42

r-hFSH

Comparable implantation rate, pregnancy rates and number of oocytes retrieved between groups

N. Andersen et al. 2008 [65]

RCT subgroup analysis

August 2003 to November 2004

Denmark

Sweden

Norway

Finland

(multi-centre)

GnRH agonist long

Nafarelin

200 μg twice a day

N = 100

Age 35–40 years

Group A

N = 49

r-hFSH +r-hLH

r-hLH started at stimulation day 6

r-hLH dosage 150 IU

Group B

N = 51

r-hFSH

Comparable clinical pregnancy rate, implantation rate and number of oocytes retrieved between groups

Matorras et al. 2009 [64]

RCT

January 2005 to November 2006

Spain

(single-centre)

GnRH agonist

long

Triptorelin

0.1 mg/day

N = 131

Age 35–39 years

Group B

N = 63

r-hFSH + r-hLH

r-hLH started at stimulation day 6

r-hLH dosage

150 IU

Group A

N = 68

r-hFSH

Significantly higher implantation rate, live birth rate in r-hLH supplemented group.

Higher clinical pregnancy rate in r-hLH supplemented group

Bosch et al. 2011 [9]

RCT

January 2005 to December 2007

Spain

(single-centre)

GnRH

antagonist

Cetrorelix 0.25 mg/day

OC during the cycle before stimulation

N = 292

Age 36–39 years

Group A

N = 150

r-hFSH + r-hLH

r-hLH dosage

75 IU

r-hLH started at stimulation day 1

Group B

N = 142

r-hFSH

Significantly lower number of oocytes retrieved in r-hLH supplemented group

Significantly higher implantation rate in r-hLH supplemented group

Higher clinical pregnancy rates in r-hLH supplemented group

Fabregues et al. 2011 [68]

RCT

January 2007 to February 2008

Spain

(single-centre)

GnRH agonist long

Triptorelin

0.1 mg /day

N = 187

Age 35–41 years

Group A1

N = 62

r-hFSH + r-hLH

Group A2

n = 63

r-hFSH + r-hLH

r-hLH started at stimulation day 6 in A1 and A2

Group A1 r-hLH dosage 37.5 IU

Group A2 r-hLH dosage 75 IU

Group B

N = 62

r-hFSH

Significantly lower number of oocytes retrieved and MII oocytes in r-hLH supplemented group

Comparable implantation rate and pregnancy rates between groups

Konig et al. 2013 [36]

RCT

January 2004 to September 2010

Netherlands

(multi-centre)

GnRH

antagonist

Cetrorelix

0.25 mg/day

N = 253

Age 35–43 years

Group A

N = 125

r-hFSH + r-hLH

r-hLH started at stimulation day 6

r-hLH dosage

150 IU

Group B

N = 128

r-hFSH

Comparable clinical pregnancy rate, implantation rate and n oocytes retrieved between groups

Vuong et al. 2015 [37]

RCT

October 2012 to June 2014

Vietnam

(single-centre)

GnRH

antagonist

Cetrorelix

N = 240

Age ≥ 35 years

Group A

N = 120

r-hFSH + r-hLH

r-hLH started at stimulation day 6

r-hLH dosage

75 IU

Group B

N = 120

r-hFSH

Comparable clinical pregnancy rate, implantation rate and number of oocytes retrieved between groups

Younis et al. 2016 [66]

RCT

April 2010 to April 2013

Israel

(single-centre)

GnRH antagonist

Cetrorelix

0.25 mg/day

N = 62

Age 35–44 years

Group A

N = 32

r-hFSH +r-hLH

r-hLH started with antagonist

r-hLH dosage

r-hFSH r-hLH ratio 2:1

Group B

N = 30

r-hFSH

Comparable clinical pregnancy rate, implantation rate and number of oocytes retrieved between groups

Humaidan et al. 2017 [71]

RCT

January 2014 and February 2015

Denmark

(multi-centre)

GnRH agonist long

Triptorelin acetate 0.1 mg

N = 821

Age 35–41 years

BMI 18–31 kg/m2

Poor response according the Bologna criteria

Group A

N = 405

r-hFSH + r-hLH

r-hLH started at stimulation day 1

r-hLH dosage

r-hFSH r-hLH ratio 2:1

Group B

N = 416

r-hFSH

Comparable number of oocytes retrieved

Continuous data are presented as mean ± standard deviation or median value when specified; categorical data are presented as percentage or Odds Ratio

n.a not available, r-hFSH recombinant human follicle stimulating hormone, r-hLH recombinant human luteinizing hormone; ≈: comparable, NS no significant, OR odds ratio, CI confidence interval, p p value