GnRH agonist versus GnRH antagonist in assisted reproduction cycles: oocyte morphology

Ana Marcia M Cota, Joao Batista A Oliveira, Claudia G Petersen, Ana L Mauri, Fabiana C Massaro, Liliane F I Silva, Andreia Nicoletti, Mario Cavagna, Ricardo L R Baruffi, José G Franco Jr, Ana Marcia M Cota, Joao Batista A Oliveira, Claudia G Petersen, Ana L Mauri, Fabiana C Massaro, Liliane F I Silva, Andreia Nicoletti, Mario Cavagna, Ricardo L R Baruffi, José G Franco Jr

Abstract

Background: The selection of developmentally competent human gametes may increase the efficiency of assisted reproduction. Spermatozoa and oocytes are usually assessed according to morphological criteria. Oocyte morphology can be affected by the age, genetic characteristics, and factors related to controlled ovarian stimulation. However, there is a lack of evidence in the literature concerning the effect of gonadotropin-releasing hormone (GnRH) analogues, either agonists or antagonists, on oocyte morphology. The aim of this randomized study was to investigate whether the prevalence of oocyte dysmorphism is influenced by the type of pituitary suppression used in ovarian stimulation.

Methods: A total of 64 patients in the first intracytoplasmic sperm injection (ICSI) cycle were prospectively randomized to receive treatment with either a GnRH agonist with a long-term protocol (n: 32) or a GnRH antagonist with a multi-dose protocol (n: 32). Before being subjected to ICSI, the oocytes at metaphase II from both groups were morphologically analyzed under an inverted light microscope at 400x magnification. The oocytes were classified as follows: normal or with cytoplasmic dysmorphism, extracytoplasmic dysmorphism, or both. The number of dysmorphic oocytes per total number of oocytes was analyzed.

Results: Out of a total of 681 oocytes, 189 (27.8%) were morphologically normal, 220 (32.3%) showed cytoplasmic dysmorphism, 124 (18.2%) showed extracytoplasmic alterations, and 148 (21.7%) exhibited both types of dysmorphism. No significant difference in oocyte dysmorphism was observed between the agonist- and antagonist-treated groups (P>0.05). Analysis for each dysmorphism revealed that the most common conditions were alterations in polar body shape (31.3%) and the presence of diffuse cytoplasmic granulations (22.8%), refractile bodies (18.5%) and central cytoplasmic granulations (13.6%). There was no significant difference among individual oocyte dysmorphisms in the agonist- and antagonist-treated groups (P>0.05).

Conclusions: Our randomized data indicate that in terms of the quality of oocyte morphology, there is no difference between the antagonist multi-dose protocol and the long-term agonist protocol. If a GnRH analogue used for pituitary suppression in IVF cycles influences the prevalence of oocyte dysmorphisms, there does not appear to be a difference between the use of an agonist as opposed to an antagonist.

Figures

Figure 1
Figure 1
Oocytes with normal and abnormal morphology: (A) normal oocyte, (B) black arrow: smooth endoplasmic reticulum (SER) aggregations; white arrow: abnormal polar body (C) large perivitelline space (D) abnormal oocyte shape (E) black arrow: central cytoplasmic granulation; white arrow: abnormal polar body (F) cytoplasmic vacuoles (G) black arrow: refractile bodies; white arrow: smooth endoplasmic reticulum (SER) aggregations (H) black arrow: dark thick zona pellucida and cytoplasm; white arrow: abnormal polar body.

References

    1. Rienzi L, Ubaldi FM, Iacobelli M, Minasi MG, Romano S, Ferrero S, Sapienza F, Baroni E, Litwicka K, Greco E. Significance of metaphase II human oocyte morphology on ICSI outcome. Fertil Steril. 2008;90:1692–1700.
    1. de Bruin JP, Dorland M, Spek ER, Posthuma G, van Haaften M, Looman CW, te Velde ER. Age-related changes in the ultrastructure of the resting follicle pool in human ovaries. Biol Reprod. 2004;70:419–424.
    1. Rashidi BH, Sarvi F, Tehrani ES, Zayeri F, Movahedin M, Khanafshar N. The effect of HMG and recombinant human FSH on oocyte quality: a randomized single-blind clinical trial. Eur J Obstet Gynecol Reprod Biol. 2005;120:190–194.
    1. Murber A, Fancsovits P, Ledo N, Gilan ZT, Rigo J, Urbancsek J. Impact of GnRH analogues on oocyte/embryo quality and embryo development in in vitro fertilization/intracytoplasmic sperm injection cycles: a case control study. Reprod Biol Endocrinol. 2009;7:103.
    1. Janssens RM, Lambalk CB, Vermeiden JP, Schats R, Bernards JM, Rekers-Mombarg LT, Schoemaker J. Dose-finding study of triptorelin acetate for prevention of a premature LH surge in IVF: a prospective, randomized, double-blind, placebo-controlled study. Hum Reprod. 2000;15:2333–2340.
    1. Sbracia M, Colabianchi J, Giallonardo A, Giannini P, Piscitelli C, Morgia F, Montigiani M, Schimberni M. Cetrorelix protocol versus gonadotropin-releasing hormone analog suppression long protocol for superovulation in intracytoplasmic sperm injection patients older than 40. Fertil Steril. 2009;91:1842–1847.
    1. Aboulghar M, Mansour R, Al-Inany H, Abou-Setta AM, Mourad L, Serour G. Paternal age and outcome of intracytoplasmic sperm injection. Reprod Biomed Online. 2007;14:588–592.
    1. Cheung LP, Lam PM, Lok IH, Chiu TT, Yeung SY, Tjer CC, Haines CJ. GnRH antagonist versus long GnRH agonist protocol in poor responders undergoing IVF: a randomized controlled trial. Hum Reprod. 2005;20:616–621.
    1. The European Middle East Orgalutran® Study Group. Comparable clinical outcome using the GnRH antagonist ganirelix or a long protocol of the GnRH agonist triptorelin for the prevention of premature LH surges in women undergoing ovarian stimulation. Hum Reprod. 2001;16:644–651.
    1. Kadoch IJ, Al-Khaduri M, Phillips SJ, Lapensee L, Couturier B, Hemmings R, Bissonnette F. Spontaneous ovulation rate before oocyte retrieval in modified natural cycle IVF with and without indomethacin. Reprod Biomed Online. 2008;16:245–249.
    1. Bauman R, Mihaljevic D, Kupesic S, Kurjak A. In vitro fertilization in spontaneous cycles–our experience. Eur J Obstet Gynecol Reprod Biol. 2002;102:184–187.
    1. Huirne JA, Homburg R, Lambalk CB. Are GnRH antagonists comparable to agonists for use in IVF? Hum Reprod. 2007;22:2805–2813.
    1. Bodri D, Sunkara SK, Coomarasamy A. Gonadotropin-releasing hormone agonists versus antagonists for controlled ovarian hyperstimulation in oocyte donors: a systematic review and meta-analysis. Fertil Steril. 2011;95:164–169.
    1. Olivennes F, Belaisch-Allart J, Emperaire JC, Dechaud H, Alvarez S, Moreau L, Nicollet B, Zorn JR, Bouchard P, Frydman R. Prospective, randomized, controlled study of in vitro fertilization-embryo transfer with a single dose of a luteinizing hormone-releasing hormone (LH-RH) antagonist (cetrorelix) or a depot formula of an LH-RH agonist (triptorelin) Fertil Steril. 2000;73:314–320.
    1. Griesinger G, Felberbaum RE, Schultze-Mosgau A, Diedrich K. Gonadotropin-releasing hormone antagonists for assisted reproductive techniques: are there clinical differences between agents? Drugs. 2004;64:563–575.
    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;83:1607–1611.
    1. Griesinger G, Felberbaum R, Diedrich K. GnRH antagonists in ovarian stimulation: a treatment regimen of clinicians’ second choice? Data from the German national IVF registry. Hum Reprod. 2005;20:2373–2375.
    1. Simon C, Oberye J, Bellver J, Vidal C, Bosch E, Horcajadas JA, Murphy C, Adams S, Riesewijk A, Mannaerts B, Pellicer A. Similar endometrial development in oocyte donors treated with either high- or standard-dose GnRH antagonist compared to treatment with a GnRH agonist or in natural cycles. Hum Reprod. 2005;20:3318–3327.
    1. Martinez-Conejero JA, Simon C, Pellicer A, Horcajadas JA. Is ovarian stimulation detrimental to the endometrium? Reprod Biomed Online. 2007;15:45–50.
    1. Pu D, Wu J, Liu J. Comparisons of GnRH antagonist versus GnRH agonist protocol in poor ovarian responders undergoing IVF. Hum Reprod. 2011;26:2742–2749.
    1. Takahashi K, Mukaida T, Tomiyama T, Goto T, Oka C. GnRH antagonist improved blastocyst quality and pregnancy outcome after multiple failures of IVF/ICSI-ET with a GnRH agonist protocol. J Assist Reprod Genet. 2004;21:317–322.
    1. Maheshwari A, Gibreel A, Siristatidis CS, Bhattacharya S. Gonadotrophin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction. Cochrane Database Syst Rev. 2011. p. CD006919.
    1. Humaidan P, Papanikolaou EG, Kyrou D, Alsbjerg B, Polyzos NP, Devroey P, Fatemi HM. The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives. Reprod Biomed Online. 2012;24:134–141.
    1. Brus L, Lambalk CB, de Koning J, Helder MN, Janssens RM, Schoemaker J. Specific gonadotrophin-releasing hormone analogue binding predominantly in human luteinized follicular aspirates and not in human pre-ovulatory follicles. Hum Reprod. 1997;12:769–773.
    1. Cheung LW, Wong AS. Gonadotropin-releasing hormone: GnRH receptor signaling in extrapituitary tissues. FEBS J. 2008;275:5479–5495.
    1. Otsuki J, Okada A, Morimoto K, Nagai Y, Kubo H. The relationship between pregnancy outcome and smooth endoplasmic reticulum clusters in MII human oocytes. Hum Reprod. 2004;19:1591–1597.
    1. De Sutter P, Dozortsev D, Qian C, Dhont M. Oocyte morphology does not correlate with fertilization rate and embryo quality after intracytoplasmic sperm injection. Hum Reprod. 1996;11:595–597.
    1. Alikani M, Palermo G, Adler A, Bertoli M, Blake M, Cohen J. Intracytoplasmic sperm injection in dysmorphic human oocytes. Zygote. 1995;3:283–288.
    1. Yakin K, Balaban B, Isiklar A, Urman B. Oocyte dysmorphism is not associated with aneuploidy in the developing embryo. Fertil Steril. 2007;88:811–816.
    1. Balaban B, Urman B. Effect of oocyte morphology on embryo development and implantation. Reprod Biomed Online. 2006;12:608–615.
    1. Van Blerkom J, Henry G. Oocyte dysmorphism and aneuploidy in meiotically mature human oocytes after ovarian stimulation. Hum Reprod. 1992;7:379–390.
    1. Balaban B, Urman B, Sertac A, Alatas C, Aksoy S, Mercan R. Oocyte morphology does not affect fertilization rate, embryo quality and implantation rate after intracytoplasmic sperm injection. Hum Reprod. 1998;13:3431–3433.
    1. Xia P. Intracytoplasmic sperm injection: correlation of oocyte grade based on polar body, perivitelline space and cytoplasmic inclusions with fertilization rate and embryo quality. Hum Reprod. 1997;12:1750–1755.
    1. Balaban B, Ata B, Isiklar A, Yakin K, Urman B. Severe cytoplasmic abnormalities of the oocyte decrease cryosurvival and subsequent embryonic development of cryopreserved embryos. Hum Reprod. 2008;23:1778–1785.
    1. Ebner T, Moser M, Tews G. Is oocyte morphology prognostic of embryo developmental potential after ICSI? Reprod Biomed Online. 2006;12:507–512.
    1. Ebner T, Yaman C, Moser M, Sommergruber M, Feichtinger O, Tews G. Prognostic value of first polar body morphology on fertilization rate and embryo quality in intracytoplasmic sperm injection. Hum Reprod. 2000;15:427–430.
    1. Ten J, Mendiola J, Vioque J, de Juan J, Bernabeu R. Donor oocyte dysmorphisms and their influence on fertilization and embryo quality. Reprod Biomed Online. 2007;14:40–48.
    1. Serhal PF, Ranieri DM, Kinis A, Marchant S, Davies M, Khadum IM. Oocyte morphology predicts outcome of intracytoplasmic sperm injection. Hum Reprod. 1997;12:1267–1270.
    1. Kahraman S, Yakin K, Donmez E, Samli H, Bahce M, Cengiz G, Sertyel S, Samli M, Imirzalioglu N. Relationship between granular cytoplasm of oocytes and pregnancy outcome following intracytoplasmic sperm injection. Hum Reprod. 2000;15:2390–2393.
    1. Meriano JS, Alexis J, Visram-Zaver S, Cruz M, Casper RF. Tracking of oocyte dysmorphisms for ICSI patients may prove relevant to the outcome in subsequent patient cycles. Hum Reprod. 2001;16:2118–2123.
    1. Farhi J, Nahum H, Weissman A, Zahalka N, Glezerman M, Levran D. Coarse granulation in the perivitelline space and IVF-ICSI outcome. J Assist Reprod Genet. 2002;19:545–549.
    1. Ebner T, Moser M, Sommergruber M, Gaiswinkler U, Shebl O, Jesacher K, Tews G. Occurrence and developmental consequences of vacuoles throughout preimplantation development. Fertil Steril. 2005;83:1635–1640.
    1. Otsuki J, Nagai Y, Chiba K. Lipofuscin bodies in human oocytes as an indicator of oocyte quality. J Assist Reprod Genet. 2007;24:263–270.
    1. Wilding M, Di Matteo L, D’Andretti S, Montanaro N, Capobianco C, Dale B. An oocyte score for use in assisted reproduction. J Assist Reprod Genet. 2007;24:350–358.
    1. Navarro PA, de Araujo MM, de Araujo CM, Rocha M, dos Reis R, Martins W. Relationship between first polar body morphology before intracytoplasmic sperm injection and fertilization rate, cleavage rate, and embryo quality. Int J Gynaecol Obstet. 2009;104:226–229.
    1. Setti AS, Figueira RC, Braga DP, Colturato SS, Iaconelli A, Borges E. Relationship between oocyte abnormal morphology and intracytoplasmic sperm injection outcomes: a meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2011;159:364–370.
    1. Rienzi L, Vajta G, Ubaldi F. Predictive value of oocyte morphology in human IVF: a systematic review of the literature. Hum Reprod Update. 2011;17:34–45.
    1. Hassan-Ali H, Hisham-Saleh A, El-Gezeiry D, Baghdady I, Ismaeil I, Mandelbaum J. Perivitelline space granularity: a sign of human menopausal gonadotrophin overdose in intracytoplasmic sperm injection. Hum Reprod. 1998;13:3425–3430.
    1. Ciotti PM, Notarangelo L, Morselli-Labate AM, Felletti V, Porcu E, Venturoli S. First polar body morphology before ICSI is not related to embryo quality or pregnancy rate. Hum Reprod. 2004;19:2334–2339.
    1. De Santis L, Cino I, Rabellotti E, Calzi F, Persico P, Borini A, Coticchio G. Polar body morphology and spindle imaging as predictors of oocyte quality. Reprod Biomed Online. 2005;11:36–42.
    1. Chamayou S, Ragolia C, Alecci C, Storaci G, Maglia E, Russo E, Guglielmino A. Meiotic spindle presence and oocyte morphology do not predict clinical ICSI outcomes: a study of 967 transferred embryos. Reprod Biomed Online. 2006;13:661–667.
    1. Figueira RCS, Braga DPAF, Semiao-Francisco L, Madaschi C, Iaconelli A, Borges E. Metaphase II human oocyte morphology: contributing factors and effects on fertilization potential and embryo developmental ability in ICSI cycles. Fertil Steril. 2010;94:1115–1117.
    1. Loutradis D, Drakakis P, Kallianidis K, Milingos S, Dendrinos S, Michalas S. Oocyte morphology correlates with embryo quality and pregnancy rate after intracytoplasmic sperm injection. Fertil Steril. 1999;72:240–244.
    1. Mikkelsen AL, Lindenberg S. Morphology of in-vitro matured oocytes: impact on fertility potential and embryo quality. Hum Reprod. 2001;16:1714–1718.
    1. Uhm SJ, Gupta MK, Yang JH, Chung HJ, Min TS, Lee HT. Epidermal growth factor can be used in lieu of follicle-stimulating hormone for nuclear maturation of porcine oocytes in vitro. Theriogenology. 2010;73:1024–1036.
    1. Chen X, Zhou B, Yan J, Xu B, Tai P, Li J, Peng S, Zhang M, Xia G. Epidermal growth factor receptor activation by protein kinase C is necessary for FSH-induced meiotic resumption in porcine cumulus-oocyte complexes. J Endocrinol. 2008;197:409–419.
    1. Yang J, Fu M, Wang S, Chen X, Ning G, Xu B, Ma Y, Zhang M. An antisense oligodeoxynucleotide to the LH receptor attenuates FSH-induced oocyte maturation in mice. Asian-Aust J Anim Sci. 2008;21:972–979.
    1. Wang C, Xu B, Zhou B, Zhang C, Yang J, Ouyang H, Ning G, Zhang M, Shen J, Xia G. Reducing CYP51 inhibits follicle-stimulating hormone induced resumption of mouse oocyte meiosis in vitro. J Lipid ResJ Lipid Res. 2009;50:2164–2172.
    1. Franco JG, 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.
    1. Caserta D, Lisi F, Marci R, Ciardo F, Fazi A, Lisi R, Moscarini M. Does supplementation with recombinant luteinizing hormone prevent ovarian hyperstimulation syndrome in down regulated patients undergoing recombinant follicle stimulating hormone multiple follicular stimulation for IVF/ET and reduces cancellation rate for high risk of hyperstimulation? Gynecol Endocrinol. 2011;27:862–866.
    1. Ruvolo G, Bosco L, Pane A, Morici G, Cittadini E, Roccheri MC. Lower apoptosis rate in human cumulus cells after administration of recombinant luteinizing hormone to women undergoing ovarian stimulation for in vitro fertilization procedures. Fertil Steril. 2007;87:542–546.
    1. Detti L, Ambler DR, Yelian FD, Kruger ML, Diamond MP, Puscheck EE. Timing and duration of use of GnRH antagonist down-regulation for IVF/ICSI cycles have no impact on oocyte quality or pregnancy outcomes. J Assist Reprod Genet. 2008;25:177–181.
    1. Acevedo B, Sanchez M, Gomez JL, Cuadros J, Ricciarelli E, Hernandez ER. Luteinizing hormone supplementation increases pregnancy rates in gonadotropin-releasing hormone antagonist donor cycles. Fertil Steril. 2004;82:343–347.
    1. Hernandez ER. Embryo implantation and GnRH antagonists: embryo implantation: the Rubicon for GnRH antagonists. Hum Reprod. 2000;15:1211–1216.
    1. Aguiar LP, Moraes LM, Lamita RM, Marinho RM, Caetano JPJ. Correlação entre a morfologia do oócito e o desenvolvimento embrionário: Proposta de escore para qualidade embrionária. Reprod Hum. 2003;3:19–24.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe