Efficacy of Follicle-Stimulating Hormone (FSH) Alone, FSH + Luteinizing Hormone, Human Menopausal Gonadotropin or FSH + Human Chorionic Gonadotropin on Assisted Reproductive Technology Outcomes in the "Personalized" Medicine Era: A Meta-analysis

Daniele Santi, Livio Casarini, Carlo Alviggi, Manuela Simoni, Daniele Santi, Livio Casarini, Carlo Alviggi, Manuela Simoni

Abstract

Setting: Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) act on the same receptor, activating different signal transduction pathways. The role of LH or hCG addition to follicle-stimulating hormone (FSH) as well as menopausal gonadotropins (human menopausal gonadotropin; hMG) in controlled ovarian stimulation (COS) is debated.

Objective: To compare FSH + LH, or FSH + hCG or hMG vs. FSH alone on COS outcomes.

Design: A meta-analysis according to PRISMA statement and Cochrane Collaboration was performed, including prospective, controlled clinical trials published until July 2016, enrolling women treated with FSH alone or combined with other gonadotropins. Trials enrolling women with polycystic ovarian syndrome were excluded (PROSPERO registration no. CRD42016048404).

Results: Considering 70 studies, the administration of FSH alone resulted in higher number of oocytes retrieved than FSH + LH or hMG. The MII oocytes number did not change when FSH alone was compared to FSH + LH, FSH + hCG, or hMG. Embryo number and implantation rate were higher when hMG was used instead of FSH alone. Pregnancy rate was significantly higher in FSH + LH-treated group vs. others. Only 12 studies reported live birth rate, not providing protocol-dependent differences. Patients' stratification by GnRH agonist/antagonist identified patient subgroups benefiting from specific drug combinations.

Conclusion: In COS, FSH alone results in higher oocyte number. HMG improves the collection of mature oocytes, embryos, and increases implantation rate. On the other hand, LH addition leads to higher pregnancy rate. This study supports the concept of a different clinical action of gonadotropins in COS, reflecting previous in vitro data.

Keywords: assisted reproductive technology; controlled ovarian stimulation; follicle-stimulating hormone; human chorionic gonadotropin; human menopausal gonadotropin; luteinizing hormone; pregnancy rate.

Figures

Figure 1
Figure 1
Study flow chart.
Figure 2
Figure 2
Forrest plot evaluating the retrieved oocytes number comparing follicle-stimulating hormone alone to luteinizing hormone (A), human chorionic gonadotropin (B), and human menopausal gonadotropin (C).
Figure 2
Figure 2
Forrest plot evaluating the retrieved oocytes number comparing follicle-stimulating hormone alone to luteinizing hormone (A), human chorionic gonadotropin (B), and human menopausal gonadotropin (C).
Figure 3
Figure 3
Forrest plot evaluating the pregnancy rate comparing follicle-stimulating hormone alone to luteinizing hormone (A), human chorionic gonadotropin (B), and human menopausal gonadotropin (C).
Figure 3
Figure 3
Forrest plot evaluating the pregnancy rate comparing follicle-stimulating hormone alone to luteinizing hormone (A), human chorionic gonadotropin (B), and human menopausal gonadotropin (C).
Figure 4
Figure 4
Risk-of-bias graph: the authors’ judgment about each risk-of-bias item is presented as percentages across all included studies.
Figure 5
Figure 5
Overall model of meta-analysis results. Each scatter plot represents the mean differences with related confidence interval (95%) for each of assisted reproductive technology outcomes evaluated. The three lines represent the polynomial trend line. Red line shows the results with luteinizing hormone supplementation, blue line with human menopausal gonadotropin and black line with human chorionic gonadotropin.

References

    1. Ascoli M, Fanelli F, Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev (2002) 23(2):141–74.10.1210/edrv.23.2.0462
    1. Casarini L, Lispi M, Longobardi S, Milosa F, La Marca A, Tagliasacchi D, et al. LH and hCG action on the same receptor results in quantitatively and qualitatively different intracellular signalling. PLoS One (2012) 7(10):e46682.10.1371/journal.pone.0046682
    1. Casarini L, Riccetti L, De Pascali F, Nicoli A, Tagliavini S, Trenti T, et al. Follicle-stimulating hormone potentiates the steroidogenic activity of chorionic gonadotropin and the anti-apoptotic activity of luteinizing hormone in human granulosa-lutein cells in vitro. Mol Cell Endocrinol (2016) 422:103–14.10.1016/j.mce.2015.12.008
    1. Baer G, Loumaye E. Comparison of recombinant human luteinising hormone (r-hLH) and human menopausal gonadotropin (hMG) in assisted reproductive technology. Curr Med Res Opin (2003) 19(2):83–8.10.1185/030079902125001498
    1. Wong KM, Mastenbroek S, Repping S. Cryopreservation of human embryos and its contribution to in vitro fertilization success rates. Fertil Steril (2014) 102(1):19–26.10.1016/j.fertnstert.2014.05.027
    1. Alviggi C, Humaidan P, Ezcurra D. Hormonal, functional and genetic biomarkers in controlled ovarian stimulation: tools for matching patients and protocols. Reprod Biol Endocrinol (2012) 10:9.10.1186/1477-7827-10-9
    1. Davis OK. IVF stimulation: protocols for poor responders. Methods Mol Biol (2014) 1154:329–41.10.1007/978-1-4939-0659-8_15
    1. Shrestha D, La X, Feng HL. Comparison of different stimulation protocols used in in vitro fertilization: a review. Ann Transl Med (2015) 3(10):137.10.3978/j.issn.2305-5839.2015.04.09
    1. Edwards RG, Steptoe PC. Induction of follicular growth, ovulation and luteinization in the human ovary. J Reprod Fertil Suppl (1975) 22:121–63.
    1. Cedrin-Durnerin I, Grange-Dujardin D, Laffy A, Parneix I, Massin N, Galey J, et al. Recombinant human LH supplementation during GnRH antagonist administration in IVF/ICSI cycles: a prospective randomized study. Hum Reprod (2004) 19(9):1979–84.10.1093/humrep/deh369
    1. Propst AM, Hill MJ, Bates GW, Palumbo M, Van Horne AK, Retzloff MG. Low-dose human chorionic gonadotropin may improve in vitro fertilization cycle outcomes in patients with low luteinizing hormone levels after gonadotropin-releasing hormone antagonist administration. Fertil Steril (2011) 96(4):898–904.10.1016/j.fertnstert.2011.06.069
    1. Balasch J, Fabregues F. LH in the follicular phase: neither too high nor too low. Reprod Biomed Online (2006) 12(4):406–15.10.1016/S1472-6483(10)61991-8
    1. Hompes PG, Broekmans FJ, Hoozemans DA, Schats R, FIRM group . Effectiveness of highly purified human menopausal gonadotropin vs. recombinant follicle-stimulating hormone in first-cycle in vitro fertilization-intracytoplasmic sperm injection patients. Fertil Steril (2008) 89(6):1685–93.10.1016/j.fertnstert.2007.05.039
    1. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials (1996) 17(1):1–12.10.1016/0197-2456(95)00134-4
    1. Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod (2011) 26(7):1768–74.10.1093/humrep/der106
    1. Drakopoulos P, Blockeel C, Stoop D, Camus M, de Vos M, Tournaye H, et al. Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod (2016) 31(2):370–6.10.1093/humrep/dev316
    1. Toftager M, Bogstad J, Løssl K, Prætorius L, Zedeler A, Bryndorf T, et al. Cumulative live birth rates after one ART cycle including all subsequent frozen-thaw cycles in 1050 women: secondary outcome of an RCT comparing GnRH-antagonist and GnRH-agonist protocols. Hum Reprod (2017) 32(3):556–67.10.1093/humrep/dew358
    1. Filicori M, Cognigni GE, Pocognoli P, Tabarelli C, Spettoli D, Taraborrelli S, et al. Modulation of folliculogenesis and steroidogenesis in women by graded menotrophin administration. Hum Reprod (2002) 17(8):2009–15.10.1093/humrep/17.8.2009
    1. Ku SY, Suh CS, Kim SH, Choi YM, Kim JG, Moon SY. A pilot study of the use of low dose human menopausal gonadotropin in ovulation induction. Eur J Obstet Gynecol Reprod Biol (2003) 109(1):55–9.10.1016/S0301-2115(02)00476-1
    1. Ferraretti AP, Gianaroli L, Magli MC, D’Angelo A, Farfalli V, Montanaro N. Exogenous luteinizing hormone in controlled ovarian hyperstimulation for assisted reproduction techniques. Fertil Steril (2004) 82(6):1521–6.10.1016/j.fertnstert.2004.06.041
    1. Kocak M, Dilbaz B, Demir B, Tasci Y, Tarcan A, Dede S, et al. Lyophilised hMG versus rFSH in women with unexplained infertility undergoing a controlled ovarian stimulation with intrauterine insemination: a prospective, randomised study. Gynecol Endocrinol (2010) 26(6):429–34.10.3109/09513591003632175
    1. Sagnella F, Moro F, Lanzone A, Tropea A, Martinez D, Capalbo A, et al. A prospective randomized noninferiority study comparing recombinant FSH and highly purified menotropin in intrauterine insemination cycles in couples with unexplained infertility and/or mild-moderate male factor. Fertil Steril (2011) 95(2):689–94.10.1016/j.fertnstert.2010.08.044
    1. Rashidi M, Aaleyasin A, Aghahosseini M, Loloi S, Kokab A, Najmi Z. Advantages of recombinant follicle-stimulating hormone over human menopausal gonadotropin for ovarian stimulation in intrauterine insemination: a randomized clinical trial in unexplained infertility. Eur J Obstet Gynecol Reprod Biol (2013) 169(2):244–7.10.1016/j.ejogrb.2013.03.002
    1. Moro F, Scarinci E, Palla C, Romani F, Familiari A, Tropea A, et al. Highly purified hMG versus recombinant FSH plus recombinant LH in intrauterine insemination cycles in women >/=35 years: a RCT. Hum Reprod (2015) 30(1):179–85.10.1093/humrep/deu302
    1. Muller T, Gromoll J, Simoni M. Absence of exon 10 of the human luteinizing hormone (LH) receptor impairs LH, but not human chorionic gonadotropin action. J Clin Endocrinol Metab (2003) 88(5):2242–9.10.1210/jc.2002-021946
    1. Grzesik P, Teichmann A, Furkert J, Rutz C, Wiesner B, Kleinau G, et al. Differences between lutropin-mediated and choriogonadotropin-mediated receptor activation. FEBS J (2014) 281(5):1479–92.10.1111/febs.12718
    1. Grzesik P, Kreuchwig A, Rutz C, Furkert J, Wiesner B, Schuelein R, et al. Differences in signal activation by LH and hCG are mediated by the LH/CG receptor’s extracellular hinge region. Front Endocrinol (2015) 6:140.10.3389/fendo.2015.00140
    1. Huhtaniemi IT, Catt KJ. Differential binding affinities of rat testis luteinizing hormone (LH) receptors for human chorionic gonadotropin, human LH, and ovine LH. Endocrinology (1981) 108(5):1931–8.10.1210/endo-108-5-1931
    1. Gupta C, Chapekar T, Chhabra Y, Singh P, Sinha S, Luthra K. Differential response to sustained stimulation by hCG & LH on goat ovarian granulosa cells. Indian J Med Res (2012) 135:331–40.
    1. Amsterdam A, Gold RS, Hosokawa K, Yoshida Y, Sasson R, Jung Y, et al. Crosstalk among multiple signaling pathways controlling ovarian cell death. Trends Endocrinol Metab (1999) 10(7):255–62.10.1016/S1043-2760(99)00164-2
    1. Casarini L, Reiter E, Simoni M. beta-arrestins regulate gonadotropin receptor-mediated cell proliferation and apoptosis by controlling different FSHR or LHCGR intracellular signaling in the hGL5 cell line. Mol Cell Endocrinol (2016) 437:11–21.10.1016/j.mce.2016.08.005
    1. Zech NH, Zech M, Baldauf S, Comploj G, Murtinger M, Spitzer D, et al. Ovarian stimulation in ART – unwinding pressing issues. Minerva Ginecol (2015) 67(2):127–47.
    1. Detti L, Saed GM, Fletcher NM, Kruger ML, Brossoit M, Diamond MP. Endometrial morphology and modulation of hormone receptors during ovarian stimulation for assisted reproductive technology cycles. Fertil Steril (2011) 95(3):1037–41.10.1016/j.fertnstert.2010.12.025
    1. Dewailly D, Robin G, Peigne M, Decanter C, Pigny P, Catteau-Jonard S. Interactions between androgens, FSH, anti-Mullerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary. Hum Reprod Update (2016) 22:709–22.10.1093/humupd/dmw027
    1. Ting AY, Xu J, Stouffer RL. Differential effects of estrogen and progesterone on development of primate secondary follicles in a steroid-depleted milieu in vitro. Hum Reprod (2015) 30(8):1907–17.10.1093/humrep/dev119
    1. Ezcurra D, Humaidan P. A review of luteinising hormone and human chorionic gonadotropin when used in assisted reproductive technology. Reprod Biol Endocrinol (2014) 12:95.10.1186/1477-7827-12-95
    1. Lehert P, Schertz JC, Ezcurra D. Recombinant human follicle-stimulating hormone produces more oocytes with a lower total dose per cycle in assisted reproductive technologies compared with highly purified human menopausal gonadotrophin: a meta-analysis. Reprod Biol Endocrinol (2010) 8:112.10.1186/1477-7827-8-112
    1. Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev (2016) 4:CD001750.10.1002/14651858.CD001750.pub4
    1. Orvieto R, Patrizio P. GnRH agonist versus GnRH antagonist in ovarian stimulation: an ongoing debate. Reprod Biomed Online (2013) 26(1):4–8.10.1016/j.rbmo.2012.11.001
    1. Rabinson J, Meltcer S, Zohav E, Gemer O, Anteby EY, Orvieto R. GnRH agonist versus GnRH antagonist in ovarian stimulation: the influence of body mass index on in vitro fertilization outcome. Fertil Steril (2008) 89(2):472–4.10.1016/j.fertnstert.2007.03.007
    1. Berkkanoglu M, Ozgur K. What is the optimum maximal gonadotropin dosage used in microdose flare-up cycles in poor responders? Fertil Steril (2010) 94(2):662–5.10.1016/j.fertnstert.2009.03.027
    1. Alama P, Bellver J, Vidal C, Giles J. GnRH analogues in the prevention of ovarian hyperstimulation syndrome. Int J Endocrinol Metab (2013) 11(2):107–16.10.5812/ijem.5034
    1. Fauser BC, Devroey P. Why is the clinical acceptance of gonadotropin-releasing hormone antagonist cotreatment during ovarian hyperstimulation for in vitro fertilization so slow? Fertil Steril (2005) 83(6):1607–11.10.1016/j.fertnstert.2005.02.011
    1. Gianaroli L, Racowsky C, Geraedts J, Cedars M, Makrigiannakis A, Lobo RA. Best practices of ASRM and ESHRE: a journey through reproductive medicine. Fertil Steril (2012) 98(6):1380–94.10.1016/j.fertnstert.2012.07.1164
    1. La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update (2014) 20(1):124–40.10.1093/humupd/dmt037
    1. Reindollar RH, Regan MM, Neumann PJ, Levine BS, Thornton KL, Alper MM, et al. A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial. Fertil Steril (2010) 94(3):888–99.10.1016/j.fertnstert.2009.04.022
    1. Goldman MB, Thornton KL, Ryley D, Alper MM, Fung JL, Hornstein MD, et al. A randomized clinical trial to determine optimal infertility treatment in older couples: the Forty and Over Treatment Trial (FORT-T). Fertil Steril (2014) 101(6):e1571–2.10.1016/j.fertnstert.2014.03.012
    1. Crawford S, Boulet SL, Mneimneh AS, Perkins KM, Jamieson DJ, Zhang Y, et al. Costs of achieving live birth from assisted reproductive technology: a comparison of sequential single and double embryo transfer approaches. Fertil Steril (2016) 105(2):444–50.10.1016/j.fertnstert.2015.10.032
    1. Humaidan P, Chin W, Rogoff D, D’Hooghe T, Longobardi S, Hubbard J, et al. Efficacy and safety of follitropin alfa/lutropin alfa in ART: a randomized controlled trial in poor ovarian responders. Hum Reprod (2017) 32(3):544–55.10.1093/humrep/dew360
    1. Papathanasiou A, Searle BJ, King NM, Bhattacharya S. Trends in ’poor responder’ research: lessons learned from RCTs in assisted conception. Hum Reprod Update (2016) 22(3).10.1093/humupd/dmw001

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner