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. 2021 Nov 22;11(11):CD000099.
doi: 10.1002/14651858.CD000099.pub4.

Growth hormone for in vitro fertilisation (IVF)

Akanksha Sood  1 , Gadha Mohiyiddeen  2 , Gaity Ahmad  3 , Cheryl Fitzgerald  4 , Andrew Watson  5 , Lamiya Mohiyiddeen  4
Affiliations

Growth hormone for in vitro fertilisation (IVF)

Akanksha Sood et al. Cochrane Database Syst Rev. .

Abstract

Background: In an effort to improve outcomes of in vitro fertilisation (IVF) cycles, the use of growth hormone (GH) has been considered as adjuvant treatment in ovarian stimulation. Improving the outcomes of IVF is especially important for women with infertility who are considered 'poor responders'. We have compared the outcomes of IVF with adjuvant GH versus no adjuvant treatment in routine use, and specifically in poor responders.

Objectives: To assess the effectiveness and safety of growth hormone as an adjunct to IVF compared to standard IVF for women with infertility SEARCH METHODS: We searched the following databases (to November 2020): Cochrane Gynaecology and Fertility (CGF) Group specialised register, CENTRAL, MEDLINE, Embase, CINAHL, Epistemonikos database and trial registers together with reference checking and contact with study authors and experts in the field to identify additional trials.

Selection criteria: We included all randomised controlled trials (RCTs) of adjuvant GH treatment in IVF compared with no adjuvant treatment for women with infertility. We excluded trials where additional adjuvant treatments were used with GH. We also excluded trials comparing different IVF protocols.

Data collection and analysis: We used standard methodological procedures recommended by Cochrane. Two review authors independently performed assessment of trial risk of bias and extraction of relevant data. The primary review outcome was live birth rate. The secondary outcomes were clinical pregnancy rate, oocytes retrieved, embryo transfer, units of gonadotropin used and adverse events, i.e. ectopic pregnancy, multiple pregnancy, ovarian hyperstimulation syndrome (OHSS), congenital anomalies, oedema.

Main results: We included 16 RCTs (1352 women). Two RCTs (80 women) studied GH in routine use, and 14 RCTs (1272 women) studied GH in poor responders. The evidence was low to very low certainty, the main limitations being risk of bias, imprecision and heterogeneity. Adjuvant growth hormone compared to no adjuvant: routine use for in vitro fertilisation (IVF) The evidence is very uncertain about the effect of GH on live birth rate per woman randomised for routine use in IVF (odds ratio (OR) 1.32, 95% confidence interval (CI) 0.40 to 4.43; I2 = 0%; 2 trials, 80 participants; very low-certainty evidence). If the chance of live birth without adjuvant GH is assumed to be 15%, the chance of live birth with GH would be between 6% and 43%. There was insufficient evidence to reach a conclusion regarding clinical pregnancy rates per woman randomised, number of women with at least one oocyte retrieved per woman randomised and embryo transfer achieved per woman randomised; reported data were unsuitable for analysis. The evidence is very uncertain about the effect of GH on mean number of oocytes retrieved in normal responders (mean difference (MD) -0.02, 95% CI -0.79 to 0.74; I2 = 0%; 2 trials, 80 participants; very low-certainty evidence). The evidence is very uncertain about the effect of GH on mean units of gonadotropin used in normal responders (MD 13.57, 95% CI -112.88 to 140.01; I2 = 0%; 2 trials, 80 participants; very low-certainty evidence). We are uncertain of the effect of GH on adverse events in normal responders. Adjuvant growth hormone compared to no adjuvant: use in poor responders for in vitro fertilisation (IVF) The evidence is very uncertain about the effect of GH on live birth rate per woman randomised for poor responders (OR 1.77, 95% CI 1.17 to 2.70; I2 = 0%; 8 trials, 737 participants; very low-certainty evidence). If the chance of live birth without adjuvant GH is assumed to be 11%, the chance of live birth with GH would be between 13% and 25%. Adjuvant GH results in a slight increase in pregnancy rates in poor responders (OR 1.85, 95% CI 1.35 to 2.53; I2 = 15%; 11 trials, 1033 participants; low-certainty evidence). The results suggest, if the pregnancy rate without adjuvant GH is assumed to be 15%, with GH the pregnancy rate in poor responders would be between 19% and 31%. The evidence suggests that GH results in little to no difference in number of women with at least one oocyte retrieved (OR 5.67, 95% CI 1.54 to 20.83; I2 = 0%; 2 trials, 148 participants; low-certainty evidence). If the chance of retrieving at least one oocyte in poor responders was 81%, with GH the chance is between 87% and 99%. There is a slight increase in mean number of oocytes retrieved with the use of GH for poor responders (MD 1.40, 95% CI 1.16 to 1.64; I2 = 87%; 12 trials, 1153 participants; low-certainty evidence). The evidence is very uncertain about the effect of GH on embryo transfer achieved (OR 2.32, 95% CI 1.08 to 4.96; I2 = 25%; 4 trials, 214 participants; very low-certainty evidence). If the chance of achieving embryo transfer is assumed to be 77%, the chance with GH will be 78% to 94%. Use of GH results in reduction of mean units of gonadotropins used for stimulation in poor responders (MD -1088.19, 95% CI -1203.20 to -973.18; I2 = 91%; 8 trials, 685 participants; low-certainty evidence). High heterogeneity in the analyses for mean number of oocytes retrieved and units of GH used suggests quite different effects according to differences including in trial protocols (populations, GH dose and schedule), so these results should be interpreted with caution. We are uncertain of the effect of GH on adverse events in poor responders as six of the 14 included trials failed to report this outcome.

Authors' conclusions: The use of adjuvant GH in IVF treatment protocols has uncertain effect on live birth rates and mean number of oocytes retrieved in normal responders. However, it slightly increases the number of oocytes retrieved and pregnancy rates in poor responders, while there is an uncertain effect on live birth rates in this group. The results however, need to be interpreted with caution, as the included trials were small and few in number, with significant bias and imprecision. Also, the dose and regimen of GH used in trials was variable. Therefore, further research is necessary to fully define the role of GH as adjuvant therapy in IVF.

Trial registration: ClinicalTrials.gov NCT01715324 NCT02179255 NCT03027843 NCT03373149 NCT03759301.

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Conflict of interest statement

AS has no conflicts of interest to declare.

GM has no conflicts of interest to declare.

GA has no conflicts of interest to declare.

CF has no conflicts of interest to declare.

AW has no conflicts of interest to declare.

LM has no conflicts of interest to declare.

Figures

1
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2
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included trials.
3
3
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
4
4
Forest plot of comparison: 1 Adjuvant GH compared to no adjuvant: routine use for IVF, outcome: 1.1 Live birth rate per woman randomised.
5
5
Forest plot of comparison: 2 Growth hormone versus no adjuvant: poor responders, outcome: 2.1 Live birth rate per woman randomised.
6
6
Forest plot of comparison: 2 Growth hormone versus no adjuvant: poor responders, outcome: 2.2 Pregnancy rate per woman randomised.
7
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10
10
Funnel plot ‐ Preganacy rate per woman randomised in poor responder group.
1.1
1.1. Analysis
Comparison 1: Adjuvant GH compared to no adjuvant: routine use for IVF, Outcome 1: Live birth rate per woman randomised
1.2
1.2. Analysis
Comparison 1: Adjuvant GH compared to no adjuvant: routine use for IVF, Outcome 2: Clinical pregnancy rate per woman randomised
1.3
1.3. Analysis
Comparison 1: Adjuvant GH compared to no adjuvant: routine use for IVF, Outcome 3: Number of women with at least one oocyte retrieved per woman randomised
1.4
1.4. Analysis
Comparison 1: Adjuvant GH compared to no adjuvant: routine use for IVF, Outcome 4: Mean number of oocytes retrieved
1.5
1.5. Analysis
Comparison 1: Adjuvant GH compared to no adjuvant: routine use for IVF, Outcome 5: Embryo transfer achieved per woman randomised
1.6
1.6. Analysis
Comparison 1: Adjuvant GH compared to no adjuvant: routine use for IVF, Outcome 6: Mean units of gonadotrophin used
2.1
2.1. Analysis
Comparison 2: Adjuvant GH compared to no adjuvant: poor responders for IVF, Outcome 1: Live birth rate per woman randomised
2.2
2.2. Analysis
Comparison 2: Adjuvant GH compared to no adjuvant: poor responders for IVF, Outcome 2: Clinical pregnancy rate per woman randomised
2.3
2.3. Analysis
Comparison 2: Adjuvant GH compared to no adjuvant: poor responders for IVF, Outcome 3: Number of women with at least one oocyte retrieved per woman randomised
2.4
2.4. Analysis
Comparison 2: Adjuvant GH compared to no adjuvant: poor responders for IVF, Outcome 4: Mean number of oocytes retrieved
2.5
2.5. Analysis
Comparison 2: Adjuvant GH compared to no adjuvant: poor responders for IVF, Outcome 5: Embryo transfer acheived per woman randomised
2.6
2.6. Analysis
Comparison 2: Adjuvant GH compared to no adjuvant: poor responders for IVF, Outcome 6: Mean units gonadotropin used
3.1
3.1. Analysis
Comparison 3: Adjuvant GH compared to no adjuvant: subgroup analysis based on age, Outcome 1: Live birth rate per woman randomised
3.2
3.2. Analysis
Comparison 3: Adjuvant GH compared to no adjuvant: subgroup analysis based on age, Outcome 2: Clinical pregnancy rate per woman randomised
3.3
3.3. Analysis
Comparison 3: Adjuvant GH compared to no adjuvant: subgroup analysis based on age, Outcome 3: No of women with at least one oocyte retrieved per woman randomised
3.4
3.4. Analysis
Comparison 3: Adjuvant GH compared to no adjuvant: subgroup analysis based on age, Outcome 4: Mean number of oocytes retrieved
3.5
3.5. Analysis
Comparison 3: Adjuvant GH compared to no adjuvant: subgroup analysis based on age, Outcome 5: Embryo transfer achieved per woman randomised
3.6
3.6. Analysis
Comparison 3: Adjuvant GH compared to no adjuvant: subgroup analysis based on age, Outcome 6: Mean units of gonadotropin used
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Balasubramanyam 2017 {published data only}
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Bhattacharya 2014 {unpublished data only}
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Blumenfeld 1994 {published data only}
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Busacca 1996 {published data only}
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Cui 2018 {published data only}
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Hazout 2009 {published data only}
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Homburg 1990a {published data only}
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Homburg 1990b {published data only}
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Homburg 1995 {published data only}
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Howles 1999 {published data only}
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Hughes 1994 {published data only}
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Jacobs 1995 {published data only}
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Latte 2013 {unpublished data only}
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Li 2020 {published data only}
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Matsumoto 2020 {published data only}
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Merdassi 2010 {published data only}
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Nayar 2018 {published data only}
    1. Nayar KD, Gupta S, Singh M, Gupta M, Kant G, Sharma N et al. Adjuvant recombinant Lh (rLH) or growth hormone (GH) to the antagonist protocol in poor responders undergoing IVF. Fertility and Sterility. Conference: 74th annual congress of the American society for reproductive medicine, ASRM 2018. Denver Colorado, USA 2018;110(4):e101-e102.
Ob'edkova 2017 {published data only}
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Owen 1991b {published data only}
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Regan 2018 {published data only}
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Rinehart 1999 {published data only}
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Sakr 2012 {published data only}
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Schoolcraft 1997 {published data only}
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Tulandi 1993 {published data only}
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Viardot‐Foucault 2016 {published data only}
    1. Viardot-Foucault V, Lye WK, Edrus E, Tan H, Nadarajah S. Poor ovarian responders' best therapeutic options: a centre's experience. Journal of Assisted Reproduction and Genetics. Conference: Translational Rproduction Biology and Clinical Reproductive Endocrinology Conference 2016. USA 2016;33(12):1694-5.
Xue‐Mei 2016 {published data only}
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Yovich 2010 {published data only}
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References to studies awaiting assessment

Bassiouny 2016 {published data only}
    1. Bassiouny YA, Dakhly DM, Bayoumi YA, Hashish NM. Does the addition of growth hormone to the in vitro fertilization/intracytoplasmic sperm injection antagonist protocol improve outcomes in poor responders? A randomized, controlled trial. Fertility and Sterility 2016;105(3):697-702. - PubMed
Bayoumi 2015 {published data only}
    1. Bayoumi Y, Dakhly DMR, Bassiouny Y, Hashish N. Addition of growth hormone to the micro flare stimulation protocol among women with poor ovarian response. International Journal of Gynaecology and Obstetrics 2015;131:305-8. - PubMed
Eftekhar 2012 {published data only}
    1. Eftekhar M, Aflatoonian A, Mohammadian F, Eftekhar T. Adjuvant growth hormone therapy in antagonist protocol in poor responders undergoing assisted reproductive technology. Archives of Gynecology and Obstetrics 2013;287:1017-21. - PubMed
Gong 2020 {published data only}
    1. Gong Y, Zhang K, Xiong D, Wei J, Tan H, Qin S. Growth hormone alleviates oxidative stress and improves the IVF outcomes of poor ovarian responders: a randomised controlled trial. Reproductive Biology and Endocrinology 2020;18(91):1-10. [PMID: ] - PMC - PubMed

References to ongoing studies

ChiCTR1800016106 {published data only}
    1. ChiCTR1800016106. Application of Growth Hormone in Patients with Poor Ovarian Response and Study of Mechanism [Application of Growth Hormone in Patients with Poor Ovarian Response and Study of Mechanism]. http://www.who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR1800016106 (first received 11 May 2018).
CTRI/2019/03/018047 {published data only}
    1. CTRI/2019/03/018047. Study to compare the effect of giving growth hormone in poor responders during IVF [Assisted reproductive technique outcomes after growth hormone supplementation in poor responders undergoing in-vitro fertilisation- a randomized controlled trial]. http://www.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2019/03/018047 (First received 12 March 2019).
NCT01715324 {unpublished data only}
    1. NCT01715324. Adjuvant Growth Therapy in in Vitro Fertilization [Adjuvant Growth Therapy in in Vitro Fertilization: A Randomized Control Trial]. https://clinicaltrials.gov/ct2/show/study/NCT01715324?term=NCT01715324&a... (First received 24 Oct 2012). [NCT01715324]
NCT02179255 {unpublished data only}
    1. NCT02179255. Human Growth Hormone Pre-treatment for 6 Weeks Prior to Ovulation Induction for IVF [An Open-Label Randomized Controlled Trial (RCT) of 6 Weeks of Human Growth Hormone (HGH) Prior to Ovulation Induction for In Vitro Fertilization (IVF)]. https://clinicaltrials.gov/ct2/show/study/NCT02179255?term=NCT02179255&a... (First received 15 Jun 2014).
NCT03027843 {unpublished data only}
    1. NCT03027843. The Effect of Growth Hormone in Assisted Reproductive Technology Clinical Outcome of Poor Responder [A Pilot Study of the Effect of Growth Hormone in Assisted Reproductive Technology Clinical Outcome of Poor Responder]. https://clinicaltrials.gov/ct2/show/NCT03027843?term=NCT03027843&dra... (First received 13 Jan 2017).
NCT03373149 {unpublished data only}
    1. NCT03373149. Growth Hormone Co-treatment Within a GnRH Antagonist Protocol in Patients With Poor Ovarian Response [Growth Hormone Co-treatment Within a GnRH Antagonist Protocol in Patients With Poor Ovarian Response]. https://clinicaltrials.gov/ct2/show/NCT03373149?term=NCT03373149&dra... (First received 7 Dec 2017).
NCT03759301 {unpublished data only}
    1. NCT03759301. Efficacy of Growth Hormone Supplementation With Gonadotrophins in IVF/ICSI for Poor Responders [Efficacy of Growth Hormone Supplementation With Gonadotrophins in IVF/ICSI for Poor Responders; a Randomized Controlled Trial]. https://clinicaltrials.gov/ct2/show/NCT03759301?term=NCT03759301&dra... (First received 22 Nov 2018).

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