Controlled Ovarian Stimulation with recombinant-FSH plus recombinant-LH vs. human Menopausal Gonadotropin based on the number of retrieved oocytes: results from a routine clinical practice in a real-life population

Alberto Revelli, Grazia Pettinau, Gemma Basso, Andrea Carosso, Alessandro Ferrero, Cecilia Dallan, Stefano Canosa, Gianluca Gennarelli, Daniela Guidetti, Claudia Filippini, Chiara Benedetto, Alberto Revelli, Grazia Pettinau, Gemma Basso, Andrea Carosso, Alessandro Ferrero, Cecilia Dallan, Stefano Canosa, Gianluca Gennarelli, Daniela Guidetti, Claudia Filippini, Chiara Benedetto

Abstract

Background: The association of recombinant FSH (rFSH) plus recombinant LH (rLH) is currently used for Controlled Ovarian Stimulation (COS) in human IVF, but its efficacy has, to date, not yet been compared to that of human Menopausal Gonadotropin (hMG), the FSH + LH activity-containing urinary drug.

Methods: Eight hundred forty-eight (848) IVF patients classified as expected "poor" or "normal" responders according to antral follicle count (AFC) and basal (day 3) FSH were treated with rFSH + rLH (2:1 ratio, n = 398, Group A) or hMG (n = 450, Group B). Data were collected under real-life practice circumstances and the pregnancy rate with fresh embryos was calculated by stratifying patients according to the number of retrieved oocytes (1-2, 3-4, 5-6, 7-8, >8).

Results: Overall, the pregnancy rate in both groups progressively improved according to the number of oocytes retrieved. When comparing patients within the same subgroup of oocyte yield, Group A and B showed a comparable outcome up to the reported highest yield (>8). When more than 8 oocytes were available, Group A had a significantly better pregnancy rate outcome. Patients' characteristics did not significantly differ between the two groups and the better outcome in the best responding patients in Group A was confirmed by a multivariable logistic regression analysis, that showed that both the use of rFSH + rLH and the total number of retrieved oocytes increased the probability of pregnancy with odd ratio (OR) of 1.628 and 1.083, respectively.

Conclusions: When comparing patients with the same number of retrieved oocytes under real-life circumstances, the association of rFSH + rLH results in a significantly higher pregnancy rate than hMG when more than 8 oocytes are retrieved. The reason(s) for this are unknown, but a more favorable effect on oocyte quality and/or endometrial receptivity could be involved.

Figures

Fig. 1
Fig. 1
Pregnancy rate per embryo transfer (PR/ET) in subgroups of patients stratified according to the number retrieved oocytes (a) or to the number of mature (MII) oocytes (b). Pale columns correspond to patients who received rFSH + rLH/2:1 (Group A, n = 398), dark columns to patients who received hMG (Group B, n = 450). *p = 0.0038; **p = 0.013

References

    1. Bosch E, Ezcurra D. Individualised controlled ovarian stimulation (iCOS): maximising success rates for assisted reproductive technology patients. Reprod Biol Endocrinol. 2011;9:82. doi: 10.1186/1477-7827-9-82.
    1. Weimer K, Enck P. Traditional and innovative experimental and clinical trial designs and their advantages and pitfalls. Handb Exp Pharmacol. 2014;225:237–272. doi: 10.1007/978-3-662-44519-8_14.
    1. Mauskopf JA, Sullivan SD, Annemans L, Caro J, Mullins CD, Nuijten M, Orlewska E, Watkins J, Trueman P. Principles of good practice for budget impact analysis: report of the ISPOR Task Force on good research practices--budget impact analysis. Value Health. 2007;10:336–347. doi: 10.1111/j.1524-4733.2007.00187.x.
    1. Payne K, Annemans L. Reflections on market access for personalized medicine: recommendations for Europe. Value Health. 2013;16:S32–8. doi: 10.1016/j.jval.2013.06.010.
    1. Al-Inany HG, Abou-Setta AM, Aboulghar MA, Mansour RT, Serour GI. Efficacy and safety of human menopausal gonadotrophins versus recombinant FSH: a meta-analysis. Reprod Biomed Online. 2008;16:81–88. doi: 10.1016/S1472-6483(10)60559-7.
    1. van Wely M, Kwan I, Burt AL, Thomas J, Vail A, Van der Veen F, Al-Inany HG. Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles. A Cochrane review. Hum Reprod Update. 2012;18:111. doi: 10.1093/humupd/dmr048.
    1. Trew GH, Brown AP, Gillard S, Blackmore S, Clewlow C, O’Donohoe P, Wasiak R. In vitro fertilisation with recombinant follicle stimulating hormone requires less IU usage compared with highly purified human menopausal gonadotrophin: results from a European retrospective observational chart review. Reprod Biol Endocrinol. 2010;8:137. doi: 10.1186/1477-7827-8-137.
    1. Franco JG, Jr, Baruffi RL, Oliveira JB, Mauri AL, Petersen CG, Contart P, Felipe V. Effects of recombinant LH supplementation to recombinant FSH during induced ovarian stimulation in the GnRH-agonist protocol: a matched case-control study. Reprod Biol Endocrinol. 2009;7:58–63. doi: 10.1186/1477-7827-7-58.
    1. Maguire M, Csokmay J, Segars J, Payson M, Armstrong A. Enough is enough! Patients who do not conceive on 600 IU/d of gonadotropins show no improvement from an additional 150 IU of LH activity. Fertil Steril. 2011;95:372–373. doi: 10.1016/j.fertnstert.2010.08.020.
    1. Fábregues F, Creus M, Peñarrubia J, Manau D, Vanrell JA, Balasch J. Effects of recombinant human luteinizing hormone supplementation on ovarian stimulation and the implantation rate in down-regulated women of advanced reproductive age. Fertil Steril. 2006;85:925–931. doi: 10.1016/j.fertnstert.2005.09.049.
    1. Barrenetxea G, Agirregoikoa JA, Jiménez MR, de Larruzea AL, Ganzabal T, Carbonero K. Ovarian response and pregnancy outcome in poor-responder women: a randomized controlled trial on the effect of luteinizing hormone supplementation on in vitro fertilization cycles. Fertil Steril. 2008;89:546–553. doi: 10.1016/j.fertnstert.2007.03.088.
    1. Check JH, Davies E, Brasile D, Choe JK, Amui J. A prospective comparison of in vitro fertilization (IVF) outcome following controlled ovarian hyperstimulation (COH) regimens using follitropin alpha exclusively or with the addition of low dose human chorionic gonadotropin (hCG) and ganirelix. Clin Exp Obstet Gynecol. 2009;36:217–218.
    1. Revelli A, Chiado’ A, Guidetti D, Bongioanni F, Rovei V, Gennarelli G. Outcome of in vitro fertilization in patients with proven poor ovarian responsiveness after early vs. mid-follicular LH exposure: a prospective, randomized, controlled study. J Assist Reprod Genet. 2012;29:869–875. doi: 10.1007/s10815-012-9804-0.
    1. König TE, van der Houwen LE, Overbeek A, Hendriks ML, Beutler-Beemsterboer SN, Kuchenbecker WK, Renckens CN, Bernardus RE, Schats R, Homburg R, Hompes PG, Lambalk CB. Recombinant LHsupplementation to a standard GnRH antagonist protocol in women of 35 years or older undergoing IVF/ICSI: a randomized controlled multicentre study. Hum Reprod. 2013;28:2804–2812. doi: 10.1093/humrep/det266.
    1. Hill MJ, Levy G, Levens ED. Does exogenous LH in ovarian stimulation improve assisted reproduction success? An appraisal of the literature. Reprod Biomed Online. 2012;24:261–271. doi: 10.1016/j.rbmo.2011.12.005.
    1. Alviggi C, Clarizia R, Mollo A, Ranieri A, De Placido G. Who needs LH in ovarian stimulation? Reprod BioMed Online. 2011;22(Suppl 1):S33–41. doi: 10.1016/S1472-6483(11)60007-2.
    1. Lehert P, Kolibianakis EM, Venetis CA, Schertz J, Saunders H, Arriagada P, Copt S, Tarlatzis B. Recombinant human follicle-stimulating hormone (r-hFSH) plus recombinant luteinizing hormone versus r-hFSH alone for ovarian stimulation during assisted reproductive technology: systematic review and meta-analysis. Reprod Biol Endocrinol. 2014;12:17. doi: 10.1186/1477-7827-12-17.
    1. Holte J, Berglund L, Milton K, Garello C, Gennarelli G, Revelli A, Bergh T. Construction of an evidence-based integrated morphology cleavage embryo score for implantation potential of embryos scored and transferred on day 2 after oocyte retrieval. Hum Reprod. 2007;22:548–557. doi: 10.1093/humrep/del403.
    1. Couzinet B, Lestrat N, Brailly S, Forest M, Schaison G. Stimulation of ovarian follicular maturation with pure follicle stimulating hormone in women with gonadotropin deficiency. J Clin Endocrinol Metab. 1988;66:552–556. doi: 10.1210/jcem-66-3-552.
    1. Schoot DC, Harlin J, Shoham Z, Mannaerts BM, Lahlou N, Bouchard P, Bennink HJ, Fauser BC. Recombinant human follicle stimulating hormone and ovarian response in gonadotropin-deficient women. Hum Reprod. 1994;9:1237–1242.
    1. Wolfenson C, Groisman J, Couto AS, Hedenfalk M, Cortvrindt RG, Smitz JE, Jespersen S. Batch-to-batch consistency of human-derived gonadotrophin preparations compared with recombinant preparations. Reprod Biomed Online. 2005;10:442–454. doi: 10.1016/S1472-6483(10)60819-X.
    1. Ascoli M, Fanelli F, Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev. 2002;232:141–174. doi: 10.1210/edrv.23.2.0462.
    1. Gadkari RA, Roy S, Rekha N, Srinivasan N, Dighe RR. Identification of a heterodimer-specific epitope present in human chorionic gonadotrophin (hCG) using a monoclonal antibody that can distinguish between hCG and human LH. J Mol Endocrinol. 2005;34:879–887. doi: 10.1677/jme.1.01683.
    1. Casarini L, Lispi M, Longobardi S, Milosa F, La Marca A, Tagliasacchi D, Pignatti E, Simoni M. LH and hCG action on the same receptor results in quantitatively and qualitatively different intracellular signalling. Plos One. 2012;7:e46682. doi: 10.1371/journal.pone.0046682.
    1. Schiffer Z, Keren-Tal I, Deutsch M, Dantes A, Aharoni D, Weinerb A, Tirosh R, Amsterdam A. Fourier analysis of differential light scattering for the quantitation of FSH response associated with structural changes in immortalized granulosa cells. Mol Cell Endocrinol. 1996;1181:145–153. doi: 10.1016/0303-7207(96)03774-4.
    1. Amsterdam A, Sasson R, Keren-Tal I, Aharoni D, Dantes A, Rimon E, Land A, Cohen T, Dor Y, Hirsh L. Alternative pathways of ovarian apoptosis: death for life. Biochem Pharmacol. 2003;668:1355–1362. doi: 10.1016/S0006-2952(03)00485-4.
    1. Ben-Ami I, Armon L, Freimann S, Strassburger D, Ron-El R, Amsterdam A. EGF-like growth factors as LH mediators in the human corpus luteum. Hum Reprod. 2009;24:176–184. doi: 10.1093/humrep/den359.
    1. Diebel ND, Bogdanove EM. Analysis of luteinizing hormone and follicle-stimulating hormone release kinetics during a dynamic secretory event, the postpartum preovulatory surge in the rat, based on quantitative changes in stored and circulating luteinizing hormone and follicle-stimulating hormone and metabolic clearance data for these hormones. Endocrinology. 1978;1033:665–673. doi: 10.1210/endo-103-3-665.
    1. Mann K, Lamerz R, Hellmann T, Kümper HJ, Staehler G, Karl HJ. Use of human chorionic gonadotropin and alpha-fetoprotein radioimmunoassays: specificity and apparent half-life determination after delivery and in patients with germ cell tumors. Oncodev Biol Med. 1980;14:301–312.
    1. Menon B, Franzo-Romain M, Damanpour S, Menon KM. Luteinizing hormone receptor mRNA down-regulation is mediated through ERK-dependent induction of RNA binding protein. Mol Endocrinol. 2011;25:282–290. doi: 10.1210/me.2010-0366.
    1. Requena A, Cruz M, Ruiz FJ, García-Velasco JA. Endocrine profile following stimulation with recombinant follicle stimulating hormone and luteinizing hormone versus highly purified human menopausal gonadotropin. Reprod Biol Endocrinol. 2014;12:10. doi: 10.1186/1477-7827-12-10.
    1. Fabregues F, Creus M, Casals G, Carmona F, Balasch J. Outcome from consecutive ICSI cycles in patients treated with recombinant human LH and those supplemented with urinary hCG-based LH activity during controlled ovarian stimulation in the long GnRH-agonist protocol. Gynecol Endocrinol. 2013;29:430–435. doi: 10.3109/09513590.2012.754873.
    1. Pacchiarotti A, Sbracia M, Frega A, Selman H, Rinaldi L, Pacchiarotti A. Urinary hMG (Meropur) versus recombinant FSH plus recombinant LH (Pergoveris) in IVF: a multicenter, prospective, randomized controlled trial. Fertil Steril. 2010;94:2467–2469. doi: 10.1016/j.fertnstert.2010.04.035.
    1. Buhler KF, Fischer R. Recombinant human LH supplementation versus supplementation with urinary hCG-based LH activity during controlled ovarian stimulation in the long GnRH-agonist protocol: a matched case-control study. Gynecol Endocrinol. 2011;28:345–350. doi: 10.3109/09513590.2011.633128.
    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;26:1768–1774. doi: 10.1093/humrep/der106.
    1. Ji J, Liu Y, Tong XH, Luo L, Ma J, Chen Z. The optimum number of oocytes in IVF treatment: an analysis of 2455 cycles in China. Hum Reprod. 2013;28:2728–34. doi: 10.1093/humrep/det303.
    1. Briggs R, Kovacs G, MacLachlan V, Motteram C, Baker HW. Can you ever collect too many oocytes? Hum Reprod. 2015;30:81–87. doi: 10.1093/humrep/deu272.
    1. Dahan MH, Agdi M, Shehata F, Son W, Tan SL. A comparison of outcomes from in vitro fertilization cycles stimulated with either recombinant luteinizing hormone (LH) or human chorionic gonadotropin acting as an LH analogue delivered as menopausal gonadotropins, in subjects with good or poor ovarian reserve: A retrospective analysis. Eur J Obstet Gynecol Reprod Biol. 2014;172:70–73. doi: 10.1016/j.ejogrb.2013.10.027.
    1. Gatta V, Tatone C, Ciriminna R, Vento M, Franchi S, d’Aurora M, Sperduti S, Cela V, Borzì P, Palermo R, Stuppia L, Artini PG. Gene expressionprofiles of cumuluscellsobtained from womentreated with recombinant human luteinizinghormone + recombinant human follicle-stimulatinghormone or highlypurified human menopausalgonadotropin versus recombinant human follicle-stimulatinghormone alone. Fertil Steril. 2013;99:2000–2008. doi: 10.1016/j.fertnstert.2013.01.150.
    1. Grøndahl ML, Borup R, Lee YB, Myrhøj V, Meinertz H, Sørensen S. Differences in gene expression of granulosa cells from women undergoing controlled ovarian hyperstimulation with either recombinant follicle-stimulating hormone or highly purified human menopausal gonadotropin. Fertil Steril. 2009;91:1820–1830. doi: 10.1016/j.fertnstert.2008.02.137.
    1. Evans J, Salamonsen LA. Too much of a good thing? Experimental evidence suggests prolonged exposure to hCG is detrimental to endometrial receptivity. Hum Reprod. 2013;28:1610–1619. doi: 10.1093/humrep/det055.
    1. Horcajadas JA, Minguez P, Dopazo J, Esteban FJ, Domínguez F, Giudice LC, Pellicer A, Simón C. Controlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications. J Clin Endocrinol Metab. 2008;93:4500–4510. doi: 10.1210/jc.2008-0588.
    1. Perrier d’Hauterive S, Berndt S, Tsampalas M, Charlet-Renard C, Dubois M, Bourgain C, Hazout A, Foidart JM, Geenen V. Dialogue between blastocyst hCG and endometrial LH/hCG receptor: which role in implantation? Gynecol Obstet Invest. 2007;64:156–160. doi: 10.1159/000101740.
    1. Kayisli UA, Selam B, Guzeloglu-Kayisli O, Demir R, Arici A. Human chorionic gonadotropin contributes to maternal immunotolerance and endometrial apoptosis by regulating Fas-Fas ligand system. J Immunol. 2003;171:2305–13. doi: 10.4049/jimmunol.171.5.2305.
    1. Fatemi HM, Kyrou D, Bourgain C, Van den Abbeel E, Griesinger G, Devroey P. Cryopreserved-thawed human embryo transfer: spontaneous natural cycle is superior to human chorionic gonadotropin-induced natural cycle. Fertil Steril. 2010;94:2054–2058. doi: 10.1016/j.fertnstert.2009.11.036.

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