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FSH replaced by low-dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques

  1. Wellington P Martins*,
  2. Andrea DD Vieira,
  3. Jaqueline BP Figueiredo,
  4. Carolina O Nastri

Editorial Group: Cochrane Menstrual Disorders and Subfertility Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 5 FEB 2013

DOI: 10.1002/14651858.CD010042.pub2


How to Cite

Martins WP, Vieira ADD, Figueiredo JBP, Nastri CO. FSH replaced by low-dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD010042. DOI: 10.1002/14651858.CD010042.pub2.

Author Information

  1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil

*Wellington P Martins, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, University of Sao Paulo, Hospital das Clinicas da FMRP-USP, 8 andar, Campus Universitario da USP, Ribeirao Preto, Sao Paulo, 14048-900, Brazil. wpmartins@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 28 MAR 2013

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Characteristics of included studies [ordered by study ID]
Aflatoonian 2012

MethodsRandomised clinical trial, single-centre, conducted in an academic setting (Iran) between March 2009 and May 2011


ParticipantsInclusion criteria: women aged < 38 years old; regular menstrual cycles (25–35 days); BMI < 30 kg/m²; normal uterus and ovaries in vaginal ultrasound; basal FSH < 10 IU/L; no severe endometriosis, no PCOS, no history of pelvic surgery; no azoospermia; and no more than 2 IVF or ICSI cycle failures

Sample size: 122 women were randomly allocated: 60 to the intervention, and 62 to the control group


InterventionsAll participants received a single injection of 3.75 mg of depot triptorelin in mid-luteal phase of a spontaneous menstrual cycle and they menstruated before the initiation of gonadotropin treatment. Gonadotropin stimulation with IM of 150–225 IU hMG per day was started from day 2 of cycle in both groups. Ovarian response was monitored by serial vaginal sonographies and evaluation of serum E2 levels

Intervention: the administration of hMG was discontinued when at least 6 follicles ≥ 12 mm were observed and E2 levels were > 600 pg/mL; hMG was displaced by 200 IU/day of hCG until final follicular maturation. A daily dose of 200 IU of hCG was administrated by diluting one 500 IU ampoule of hCG to 1 mL using normal saline and injection of 0.4 mL of this solution

Control: women received similar doses of hMG based on individual responses until the end of stimulation

In both groups, the ovulation trigger was done by IM injection of 10,000 IU of urinary hCG when at least 3 follicles ≥ 18 mm were observed. Oocyte retrieval was performed 34–36 h after hCG injection and ICSI or conventional IVF was performed appropriately. Luteal phase hormonal support consisted of daily IM injection of 100 mg progesterone in oil


OutcomesPrimary: total doses of gonadotropin and clinical pregnancy rate

Secondary: chemical pregnancy, multiple pregnancy, miscarriage, fertilisation rate, implantation rate, number of oocytes retrieved, ongoing pregnancy


NotesDid not report live birth

Clinical pregnancy was considered only in the presence of gestational sac with heart activity detected by ultrasonography

None of the 12 reported miscarriages were considered to happen in a clinical pregnancy and were considered as only chemical pregnancy only. In our review miscarriage was considered as the loss of a clinical pregnancy before 20 completed weeks of gestational age

The total number of retrieved oocytes (instead of only MII oocytes) was used for the analysis

This study was funded by Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

Implantation rate: intervention (16.67%) vs. control (15.17%); not significant


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA computer-generated list was used for randomisation

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss of follow-up

Selective reporting (reporting bias)Low riskNot suspected

Other biasLow riskNone

Ashrafi 2011

MethodsRandomised clinical trial, single-centre, conducted in an academic setting (Iran) between January 2006 to December 2008


ParticipantsInclusion criteria: women with diagnosis of PCOS (according to the Rotterdam criteria), with normal uterine cavity and patent tubes (evaluated by hysterosalpingogram, laparoscopy or hysteroscopy), with partner having a normal semen analysis (according to WHO criteria); no previous IVF or ICSI cycles; no use of gonadotropins for ovarian stimulation during the 3 previous months

Sample size: 90 women were randomly allocated: 30 to the intervention 1, 30 to the intervention 2 (not included in this review because FSH was not stopped when low-dose hCG was started), and the other 30 to the control group


InterventionsAll the groups received SC GnRH agonist injection for 14 days, after which gonadotropin stimulation was initiated. The goal of ovarian stimulation in all 3 groups was to achieve an average of 2 ovarian follicles with a mean diameter of ≥ 17 mm on the day of hCG administration

Intervention 1: rFSH until the leading follicle reached 14 mm, when it was then discontinued and low-dose hCG (200 IU/day) was initiated

Intervention 2: rFSH until the leading follicle reached 14 mm, when rFSH reduced to 75 IU and low-dose hCG (100 IU/day) was initiated. This intervention was not included in our review, because FSH was not stopped when low-dose hCG was started

Control: received rFSH 150 IU daily. The dose and duration was adjusted by monitoring follicular development and E2 levels. The maximum FSH dose was 225 IU/day

After 2 or 3 follicles reached sizes ≥ 17 mm, 10,000 IU of hCG was administered and oocyte retrieval was performed 34-36 h later


OutcomesHormonal levels (FSH, LH, E2, progesterone and testosterone), stimulation duration days, total rFSH consumption, MII oocytes retrieved, immature oocytes, total # of oocytes retrieved, # of embryos formed, # of embryos transferred, # of embryos cryopreserved, # of medium growing follicles on hCG day, # of large growing follicles on hCG day, endometrial thickness on hCG day, fertilisation rate, implantation rate, clinical pregnancy rate, multiple pregnancy rates, severe OHSS


NotesOnly Intervention 1 was used for comparison with the control group

Authors provided additional information regarding live birth, ongoing pregnancy, miscarriage and allocation concealment by e-mail

Authors failed to follow-up until birth 6/9 ongoing pregnancies in the intervention group and 7/9 ongoing pregnancies in the control group

This study was assumed to be funded by the Royan Institute of Infertility and Reproductive Health, Iran

Implantation rate: intervention 14/53 (26.4%) vs. control: 24/75 (32.0%); not significant


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised random number sequence

Allocation concealment (selection bias)High riskThe allocation was not concealed

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessors including laboratory technicians and data analysts were blinded to group assignment

Incomplete outcome data (attrition bias)
All outcomes
High riskAlthough some participants were excluded from analyses (6 in the intervention group and 3 in the control group), we were able to analyse dichotomous data respecting the ITT principle using the assumption that clinical pregnancy (and subsequent miscarriage or live birth) did not occur and that no oocyte was retrieved in the participants with cycle cancellation

However, the study was judged to be at high risk of attrition bias for live birth, because authors failed to follow-up until birth 6 of 9 ongoing pregnancies in the intervention group and 7 of 9 ongoing pregnancies in the control group

Selective reporting (reporting bias)Low riskNot suspected

Other biasLow riskNone

Blockeel 2009

MethodsRandomised clinical trial, single-centre, conducted in an academic setting (Belgium) between September 2007 and October 2008


ParticipantsInclusion criteria: women aged < 36 years; first or second treatment cycle; no request of PGD; no azoospermic partner; no serum FSH level on day 3 of the menstrual cycle > 12 IU/L

Sample size: 70 women were randomly allocated: 35 to the intervention group, and 35 to the control group


InterventionsIntervention: the administration of rFSH was discontinued when at least 6 follicles of 12 mm were observed and E2 levels were higher than 600 ng/L. rFSH was then substituted by 200 IU hCG daily (Pregnyl, Organon), until final oocyte maturation

Control: standard antagonist protocol consisting of daily injections of rFSH, follitropin beta (Puregon, Organon) at a dose of 200 IU/day and maintained for 6 consecutive days. On day 7 of the cycle (day 6 of the stimulation), SC administration of the GnRH antagonist ganirelix (Orgalutran, Organon) was started at a daily dose of 0.25 mg. From day 7 of the cycle onwards, ovarian ultrasound scans to assess follicular growth and blood sampling for E2, progesterone, FSH, LH and hCG levels, were performed on a daily basis

Final oocyte maturation was induced by the administration of 10,000 IU hCG (Pregnyl), when at least 3 follicles of 17 mm diameter were visualised on ultrasonography. Luteal phase support consisted of 600 mg of vaginally administered micronised natural progesterone (Utrogestan, Besins International) per day.

A single embryo transfer policy was applied


OutcomesPrimary: ongoing pregnancy

Secondary: basal hormonal serum values; number of cumulus–oocyte-complexes, number of metaphase II and 2-pronuclei oocytes; duration of stimulation and total cumulative dose of rFSH used; fertilisation and implantation rates in each treatment group


NotesAuthors did not wait for the delivery of 4 ongoing pregnancies (2 for each group) and did not report what happened to 1 spontaneous clinical pregnancy that occurred in the intervention group

The spontaneous clinical pregnancy that occurred in the intervention group was included in our review

The study was assumed to be funded by Univesitair Ziekenhuis Brussel, Brussel

Implantation rate: intervention 16/27 (59.2%) vs. control 14/29 (48.3%); not significant


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA computer-generated list was used for randomisation

Allocation concealment (selection bias)High riskThe list used for randomisation was concealed to the physician but not to the study nurse

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Incomplete outcome data (attrition bias)
All outcomes
High riskAlthough some participants were excluded from analyses (6 in the intervention group and 3 in the control group), we were able to analyse dichotomous data respecting the ITT principle using the assumption that clinical pregnancy (and subsequent miscarriage or live birth) did not occur and that no oocyte was retrieved in the participants with cycle cancellation.

However, the study was judged to be at high risk of attrition bias for live birth and ongoing pregnancy, because authors did not wait for the delivery of 4 ongoing pregnancies (2 for each group) and did not report what happened to 1 spontaneous clinical pregnancy that occurred in the intervention group

Selective reporting (reporting bias)Low riskNot suspected

Other biasLow riskNone

Filicori 2005a

MethodsRandomised clinical trial, single-centre, conducted in an academic setting (Italy) between February and December 2002


ParticipantsInclusion criteria: women aged 29–39 years; good general health; regular 26- to 32-day menstrual cycles; BMI of 20–25 kg/m²; pelvic ultrasound showing a uterus and ovaries of normal size and structure (no signs of PCOS); normal baseline biochemical and endocrine determinations; reproductive hormones within the normal range for the early/mid-follicular phase of the cycle; no history or signs of endometriosis; adequate number of motile sperms for ICSI could be obtained from the ejaculate; no more than 2 previous IVF or ICSI cycles; no history of poor response to gonadotropin administration; no hormonal therapy for a period of at least 3 months preceding the study

Sample size: 48 women were randomly allocated: 24 to the intervention group, and 24 to the control group


InterventionsDown-regulation with a single injection of 3.75 mg of depot Triptorelin (Decapeptyl 3.75, IPSEN), 14 days before initiating ovarian stimulation

Intervention: participants received the same amounts of recombinant FSH or hMG until at least 6 follicles > 12 mm in diameter and E2 levels 600 pg/mL were detected; then recombinant FSH/hMG were discontinued and replaced by the daily administration of low-dose hCG (Gonasi HP 250, AMSA). A daily dose of 200 IU of hCG was administered daily by diluting an ampoule of 250 IU of hCG with 1.0 mL of normal saline and then administering SC 0.8 mL of this solution

Control: recombinant FSH (Puregon/Organon, or Gonal-F/Serono) or hMG (Menogon, Ferring) at a dose of 225–300 IU/day based on individual response until the end of COH

Final maturation when 8 follicles > 18 mm and E2 levels 1500 pg/mL with 10,000 IU of hCG (Gonasi HP 5000, 2 ampoules). Oocyte retrieval was performed 35 h later. The luteal phase was supported with 50 mg/day of IM P in oil (Prontogest, AMSA)


OutcomesPrimary: amount of recombinant FSH/hMG

Secondary: FSH, E2, progesterone and testosterone; follicle number and size at ultrasound; number of oocytes retrieved; fertilisation, implantation rate and pregnancy rate


NotesThe study was assumed to be funded by University of Bologna, Italy

Implantation rate: intervention (12%) vs. control (11%); not significant


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskChoice of sealed envelopes

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAuthors did not report whether participants were excluded or did not undergo oocyte retrieval

Selective reporting (reporting bias)Low riskNot suspected

Other biasLow riskNone

Gomes 2007

MethodsRandomised clinical trial, single-centre, conducted in an academic setting (Brazil)


ParticipantsInclusion criteria: women aged 25–35 years; good general health; regular menstrual cycles; BMI of 20–25 kg/m²; FSH ≤ 10 IU/mL; infertility due to tubal factor, moderate or severe male factor, or no apparent cause; no PCOS, no endometriosis; no uterine myomas; no use of injectable hormonal contraceptive up to 6 months before stimulation; no history of previous poor ovarian response to controlled ovarian stimulation; no concomitant uterine alterations; no absence of 1 ovary

Sample size: 51 women were randomly allocated: 17 to the intervention group, and 34 to other 2 groups of 17 participants each. These 2 groups were merged as 1 control group since the only difference between them was regarding the type of FSH (urinary or recombinant)


InterventionsThe inhibition of the natural cycle with a low-dose oral contraceptive administered on the first the previous menstruation cycle and discontinued 5 days before the beginning of stimulation. A GnRH agonist, leuprolide acetate (Lupron, Abbott), 0.5 mg/day, was also used for inhibition starting 10 days before the beginning of induction and continued until the day preceding the pre-ovulatory injection of hCG. All the groups received 200 IU SC of rFSH (Puregon, Organon) daily on until the dominant follicles reached 12–13 mm in mean diameter

Intervention: daily IM doses of 200 IU hCG (Profasi, Serono). For hCG administration, 2000 IU were diluted in 10.0 mL 0.9% physiological
saline and 1.0 mL of the solution was injected

Control: participants received either daily IM injections of 225 IU hMG (Menogon; Ferring Gmbh) or daily SC 200 IU rFSH (Puregon, Organon)

Final maturation with 10,000 IU hCG IM (Choragon, Ferring Gmbh) when the presence of follicles 18–19 mm in diameter was detected. Oocyte retrieval was performed 36 h after pre-ovulatory hCG injection. The luteal phase was supplemented with 90 mg progesterone gel (8% Crinone, Fleet)


OutcomesPrimary: amount of gonadotropins needed to achieve comparable levels of folliculogenesis

Secondary: FSH, E2, prostaglandin and testosterone, number of oocytes retrieved, fertilisation, implantation rate, and pregnancy rate and total cost of treatment per embryo transferred


NotesDid not report live birth

The hMG and rFSH groups were combined into the control group

The total number of retrieved oocytes (instead of only MII oocytes) was used for the analysis

The study was assumed to be funded by University of Sao Paulo, Brazil

Implantation rate: intervention (27.3%) vs. control (16.7%); not significant


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned through computer randomisation

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss of follow-up

Selective reporting (reporting bias)Low riskNot suspected

Other biasLow riskNone

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Beretsos 2009Low-dose hCG was used before starting FSH

Berkkanoglu 2007FSH and low-dose hCG were started simultaneously

Check 2009FSH was not stopped after starting low-dose hCG

Dehghani-Firouzabady 2006Not IVF/ICSI (only intrauterine insemination)

Drakakis 2009FSH and low-dose hCG were started simultaneously

Filicori 1999FSH and low-dose hCG were started simultaneously

Filicori 2002Not IVF/ICSI (only intrauterine insemination)

Filicori 2005bFSH was not stopped after starting low-dose hCG

Koichi 2006FSH was not stopped after starting low-dose hCG

Lossl 2008Low-dose hCG was used before starting FSH

Mendes 2005Not RCT: not randomised. Additionally, the low-dose hCG group was submitted to another intervention (bromocriptine 2.5 mg) not applied to the control group

Serafini 2006FSH was not stopped after starting low-dose hCG

Thuesen 2012FSH was not stopped after starting low-dose hCG

Van Horne 2007Not RCT: observational retrospective study

 
Comparison 1. FSH replaced by low-dose hCG versus FSH throughout the controlled ovarian hyperstimulation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Live birth2130Risk Ratio (M-H, Fixed, 95% CI)1.56 [0.75, 3.25]

 2 OHSS5351Peto Odds Ratio (Peto, Fixed, 95% CI)0.30 [0.06, 1.59]

 3 Ongoing pregnancy3252Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.81, 1.60]

 4 Clinical pregnancy5351Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.92, 1.55]

 5 Miscarriage4127Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.50, 2.31]

 6 Total dose of FSH (IU)5333Mean Difference (IV, Random, 95% CI)-638.63 [-892.62, -384.65]

 7 Oocytes retrieved5351Mean Difference (IV, Fixed, 95% CI)-0.12 [1.00, 0.76]

 
Comparison 2. Analysis grouped by participant characteristics

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 OHSS5Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

    1.1 PCOS or predicted high response
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Unselected or predicted normal response
4Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 3. Analysis grouped by the drug used to prevent premature LH surge (GnRH agonist or antagonist)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 OHSS5Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

    1.1 GnRH agonist
4Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 GnRH antagonist
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Total dose of FSH5Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 GnRH agonist
4272Mean Difference (IV, Fixed, 95% CI)-686.68 [-786.31, -587.05]

    2.2 GnRH antagonist
161Mean Difference (IV, Fixed, 95% CI)-344.0 [-479.52, -208.48]

 
Comparison 4. Analysis grouped by the daily dose of FSH (≤ 150 IU/day or > 150 IU/day)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 OHSS5Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

    1.1 FSH ≤ 150 IU/day
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 FSH > 150 IU/day
4Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Summary of findings for the main comparison. Low-dose hCG compared to FSH throughout the COH for assisted reproductive techniques

Low-dose hCG compared to FSH throughout the COH for assisted reproductive techniques

Population: women undergoing assisted reproductive techniques
Intervention: low-dose hCG in the late follicular phase
Comparison: FSH throughout the COH

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)

Assumed riskCorresponding risk

FSH throughout the COHLow-dose hCG

Live birth14 per 10022 per 100
(10 to 45)
RR 1.56
(0.75 to 3.25)
130
(2 studies)
⊕⊝⊝⊝
very low1

OHSS3 per 1001 per 100
(0 to 4)
OR 0.30
(0.06 to 1.59)
351
(5 studies)
⊕⊝⊝⊝
very low2

Ongoing pregnancy32 per 10038 per 100
(27 to 53)
RR 1.17
(0.83 to 1.64)
252
(3 studies)
⊕⊕⊝⊝
low3

Clinical pregnancy35 per 10041 per 100
(32 to 54)
RR 1.19
(0.92 to 1.55)
351
(5 studies)
⊕⊕⊝⊝
low4

Miscarriage16 per 10017 per 100
(8 to 36)
RR 1.08
(0.50 to 2.31)
127
(4 studies)
⊕⊝⊝⊝
very low5

Total dose of FSHThe average FSH total consumption in control groups was 1390 IUThe average FSH total consumption in intervention groups was 639 IU lower
(893 to 385 IU lower)
333
(5 studies)
⊕⊕⊕⊝
moderate6

Oocytes retrievedThe average number of oocytes retrieved in control groups was 9.0Oocytes retrieved in intervention groups was 0.1 lower
(1.0 lower to 0.8 higher)
333
(5 studies)
⊕⊕⊕⊝
moderate7

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; COH: controlled ovarian hyperstimulation; FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin; OHSS: ovarian hyperstimulation syndrome; OR: odds ratio; RR: Risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 The evidence quality was downgraded because of very serious imprecision, and high risk of bias.
2 The evidence quality was downgraded because of very serious imprecision, inconsistency, and high risk of bias.
3 The evidence quality was downgraded because of imprecision and high risk of bias.
4 The evidence quality was downgraded because of imprecision and high risk of bias.
5 The evidence quality was downgraded because of very serious imprecision, and high risk of bias.
6 The evidence quality was downgraded because of high risk of bias.
7 The evidence quality was downgraded because of high risk of bias.