"hCG priming" effect in controlled ovarian stimulation through a long protocol

Panagiotis Beretsos, George A Partsinevelos, Eleni Arabatzi, Peter Drakakis, Depy Mavrogianni, Elli Anagnostou, Kostas Stefanidis, Aris Antsaklis, Dimitris Loutradis, Panagiotis Beretsos, George A Partsinevelos, Eleni Arabatzi, Peter Drakakis, Depy Mavrogianni, Elli Anagnostou, Kostas Stefanidis, Aris Antsaklis, Dimitris Loutradis

Abstract

Background: Recently, it has been demonstrated that, in patients down-regulated by GnRH analogues (GnRHa), a short-term pre-treatment with recombinant LH (rLH), prior to recombinant FSH (rFSH) administration, increases the number of small antral follicle prior to FSH stimulation and the yield of normally fertilized embryos. However, no data exist in the literature regarding the potential beneficial effect of "hCG priming" in controlled ovarian hyperstimulation (COH) through a long GnRH-a protocol, which binds the same receptor (LH/hCGR), though it is a much more potent compared to LH. The primary aims of this study were to assess the effect of short-term pre-rFSH administration of hCG in women entering an ICSI treatment cycle on follicular development, quality of oocytes and early embryo development. The secondary endpoints were to record the effects on endometrial quality and pregnancy rate.

Methods: Patients with a history of at least one previous unsuccessful ICSI cycle were randomly assigned into two groups to receive treatment with either a long protocol with rFSH (control group) or a long protocol with rFSH and pre-treatment with hCG (hCG group). In particular, in the latter group, a fixed 7 days course of 200 IU/day hCG was administered as soon as pituitary desensitization was confirmed.

Results: The mean number of oocytes retrieved was not significantly different between the two treatment groups, although the percentage of mature oocytes tended to be higher but not significantly different in hCG-treated patients. The percentage of patients with more than one grade 3 embryos was higher in the pre-treatment group, which also showed a higher pregnancy rate.

Conclusion: All the above clinical observations, in conjunction with previous data, suggest a point towards a beneficial "hCG priming" effect in controlled ovarian hyperstimulation through a long GnRH-a down-regulation protocol, particularly in patients with previous ART failures.

References

    1. Loutradis D, Drakakis P, Vomvolaki E, Antsaklis A. Different ovarian stimulation protocols for women with diminished ovarian reserve. J Assist Reprod Genet. 2007;24:597–611. doi: 10.1007/s10815-007-9181-2.
    1. Hillier SG. Gonadotropic control of ovarian follicular growth and development. Mol Cell Endocrinol. 2001;179:39–46. doi: 10.1016/S0303-7207(01)00469-5.
    1. Lossl K, Andersen AN, Loft A, Freiesleben NL, Bangsboll S, Andersen CY. Androgen priming using aromatase inhibitor and hCG during early-follicular-phase GnRH antagonist down-regulation in modified antagonist protocols. Hum Reprod. 2006;21:2593–2600. doi: 10.1093/humrep/del221.
    1. Shoham Z, Schacter M, Loumaye E, Weissman A, MacNamee M, Insler V. The luteinizing hormone surge - the final stage in ovulation induction: modern aspects of ovulation triggering. Fertil Steril. 1995;64:237–251.
    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;82:1521–1526. doi: 10.1016/j.fertnstert.2004.06.041.
    1. Fleming R, on behalf of the 'Luveris Pre-treatment Group'. Durnerin IC, Erb K, Hillier SG, Hugues J-N, Lyall H, Rasmussen PE, Thong J, Traynor I, Westergaard LG, et al. Pre-treatment with rhLH: respective effects on antral follicular count and ovarian response to rhFSH. Hum Reprod. 2006;21:i54.
    1. Durnerin CI, Erb K, Fleming R, Hillier H, Hillier SG, Howles CM, Hugues JN, Lass A, Lyall H, Rasmussen P, et al. Effects of recombinant LH treatment on folliculogenesis and responsiveness to FSH stimulation. Hum Reprod. 2008;23:421–426. doi: 10.1093/humrep/dem388.
    1. Sullivan MW, Stewart-Akers A, Krasnow JS, Berga SL, Zeleznik AJ. Ovarian responses in women to recombinant follicle-stimulating hormone and luteinizing hormone (LH): a role for LH in the final stages of follicular maturation. J Clin Endocrinol Metab. 1999;84:228–232. doi: 10.1210/jc.84.1.228.
    1. Esposito MA, Barnhart KT, Coutifaris C, Patrizio P. Role of periovulatory luteinizing hormone concentrations during assisted reproductive technology cycles stimulated exclusively with recombinant follicle-stimulating hormone. Fertil Steril. 2001;75:519–524. doi: 10.1016/S0015-0282(00)01745-3.
    1. Westergaard LG, Laursen SB, Andersen CY. Increased risk of early pregnancy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotrophic women undergoing assisted reproduction. Hum Reprod. 2000;15:1003–1008. doi: 10.1093/humrep/15.5.1003.
    1. Drakakis P, Loutradis D, Kallianidis K, Liapi A, Milingos S, Makrigiannakis A, Dionyssiou-Asteriou A, Michalas S. Small doses of LH activity are needed early in ovarian stimulation for better quality oocytes in IVF-ET. Eur J Obstet Gynecol Reprod Biol. 2005;121:77–80. doi: 10.1016/j.ejogrb.2004.12.021.
    1. De Placido G, Alviggi C, Mollo A, Strina I, Ranieri A, Alviggi E, Wilding M, Varricchio MT, Borrelli AL, Conforti S. Effects of recombinant LH (rLH) supplementation during controlled ovarian hyperstimulation (COH) in normogonadotrophic women with an initial inadequate response to recombinant FSH (rFSH) after pituitary downregulation. Clin Endocrinol (Oxf) 2004;60:637–643. doi: 10.1111/j.1365-2265.2004.02027.x.
    1. De Placido G, Alviggi C, Perino A, Strina I, Lisi F, Fasolino A, De Palo R, Ranieri A, Colacurci N, Mollo A. Recombinant human LH supplementation versus recombinant human FSH (rFSH) step-up protocol during controlled ovarian stimulation in normogonadotrophic women with initial inadequate ovarian response to rFSH. A multicentre, prospective, randomized controlled trial. Hum Reprod. 2005;20:390–396. doi: 10.1093/humrep/deh625.
    1. Drakakis P, Loutradis D, Kallianidis K, Bletsa R, Milingos S, Dionyssiou-Asteriou A, Michalas S. A comparative study of the effect of ovarian stimulation protocols with different gonadotropin preparations on the biological and clinical parameters of the outcome of intracytoplasmic sperm injection. Clin Exp Obstet Gynecol. 2002;29:286–289.
    1. Porter RN, Smith W, Craft IL, Abdulwahid NA, Jacobs HS. Induction of ovulation for in-vitro fertilisation using buserelin and gonadotropins. Lancet. 1984;2:1284–1285. doi: 10.1016/S0140-6736(84)92840-X.
    1. Mochtar MH, Van der V, Ziech M, van Wely M. Recombinant Luteinizing Hormone (rLH) for controlled ovarian hyperstimulation in assisted reproductive cycles. Cochrane Database Syst Rev. 2007:CD005070.
    1. Huirne JA, Lambalk CB, van Loenen AC, Schats R, Hompes PG, Fauser BC, Macklon NS. Contemporary pharmacological manipulation in assisted reproduction. Drugs. 2004;64:297–322. doi: 10.2165/00003495-200464030-00005.
    1. Branigan EF, Estes A. Use of micro-dose human chorionic gonadotropin (hCG) after clomiphene citrate (CC) to complete folliculogenesis in previous CC-resistant anovulation. Am J Obstet Gynecol. 2005;192:1890–1894. doi: 10.1016/j.ajog.2005.02.072. discussion 1894-1896.
    1. Filicori M, Cognigni GE, Tabarelli C, Pocognoli P, Taraborrelli S, Spettoli D, Ciampaglia W. Stimulation and growth of antral ovarian follicles by selective LH activity administration in women. J Clin Endocrinol Metab. 2002;87:1156–1161. doi: 10.1210/jc.87.3.1156.
    1. Koichi K, Yukiko N, Shima K, Sachiko S. Efficacy of low-dose human chorionic gonadotropin (hCG) in a GnRH antagonist protocol. J Assist Reprod Genet. 2006;23:223–228. doi: 10.1007/s10815-006-9036-2.
    1. Serafini P, Yadid I, Motta EL, Alegretti JR, Fioravanti J, Coslovsky M. Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in vitro fertilization: a prospective, randomized trial. Fertil Steril. 2006;86:830–838. doi: 10.1016/j.fertnstert.2006.02.110.
    1. Venetis CA, Kolibianakis EM, Tarlatzi TB, Tarlatzis BC. Benefits of luteinizing hormone activity in ovarian stimulation for IVF. Reprod Biomed Online. 2009;18:31–36.
    1. Weissman A, Lurie S, Zalel Y, Goldchmit R, Shoham Z. Human chorionic gonadotropin: pharmacokinetics of subcutaneous administration. Gynecol Endocrinol. 1996;10:273–276. doi: 10.3109/09513599609012319.
    1. Yen SS, Llerena O, Little B, Pearson OH. Disappearance rates of endogenous luteinizing hormone and chorionic gonadotropin in man. J Clin Endocrinol Metab. 1968;28:1763–1767. doi: 10.1210/jcem-28-12-1763.
    1. Filicori M, Fazleabas AT, Huhtaniemi I, Licht P, Rao Ch V, Tesarik J, Zygmunt M. Novel concepts of human chorionic gonadotropin: reproductive system interactions and potential in the management of infertility. Fertil Steril. 2005;84:275–284. doi: 10.1016/j.fertnstert.2005.02.033.
    1. Filicori M, Cognigni GE, Samara A, Melappioni S, Perri T, Cantelli B, Parmegiani L, Pelusi G, DeAloysio D. The use of LH activity to drive folliculogenesis: exploring uncharted territories in ovulation induction. Hum Reprod Update. 2002;8:543–557. doi: 10.1093/humupd/8.6.543.
    1. Navot D, Relou A, Birkenfeld A, Rabinowitz R, Brzezinski A, Margalioth EJ. Risk factors and prognostic variables in the ovarian hyperstimulation syndrome. Am J Obstet Gynecol. 1988;159:210–215.
    1. Fleming R, Lloyd F, Herbert M, Fenwick J, Griffiths T, Murdoch A. Effects of profound suppression of luteinizing hormone during ovarian stimulation on follicular activity, oocyte and embryo function in cycles stimulated with purified follicle stimulating hormone. Hum Reprod. 1998;13:1788–1792. doi: 10.1093/humrep/13.7.1788.
    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. doi: 10.1016/S0015-0282(99)00233-2.
    1. Human recombinant luteinizing hormone is as effective as, but safer than, urinary human chorionic gonadotropin in inducing final follicular maturation and ovulation in in vitro fertilization procedures: results of a multicenter double-blind study. J Clin Endocrinol Metab. 2001;86:2607–2618. doi: 10.1210/jc.86.6.2607.
    1. Falck B. Site of production of oestrogen in rat ovary as studied in micro-transplants. Acta Physiol Scand Suppl. 1959;47:1–101.
    1. Sasano H, Okamoto M, Mason JI, Simpson ER, Mendelson CR, Sasano N, Silverberg SG. Immunolocalization of aromatase, 17 alpha-hydroxylase and side-chain-cleavage cytochromes P-450 in the human ovary. J Reprod Fertil. 1989;85:163–169.
    1. Mannaerts B, Gordon K. Embryo implantation and GnRH antagonists: GnRH antagonists do not activate the GnRH receptor. Hum Reprod. 2000;15:1882–1883. doi: 10.1093/humrep/15.9.1882.
    1. Requena A, Herrero J, Landeras J, Navarro E, Neyro JL, Salvador C, Tur R, Callejo J, Checa MA, Farre M, et al. Use of letrozole in assisted reproduction: a systematic review and meta-analysis. Hum Reprod Update. 2008;14:571–582. doi: 10.1093/humupd/dmn033.
    1. Sungurtekin U, Jansen RP. Profound luteinizing hormone suppression after stopping the gonadotropin-releasing hormone-agonist leuprolide acetate. Fertil Steril. 1995;63:663–665.
    1. Westergaard LG, Erb K, Laursen SB, Rex S, Rasmussen PE. Human menopausal gonadotropin versus recombinant follicle-stimulating hormone in normogonadotropic women down-regulated with a gonadotropin-releasing hormone agonist who were undergoing in vitro fertilization and intracytoplasmic sperm injection: a prospective randomized study. Fertil Steril. 2001;76:543–549. doi: 10.1016/S0015-0282(01)01973-2.
    1. Loumaye E, Engrand P, Howles CM, O'Dea L. Assessment of the role of serum luteinizing hormone and estradiol response to follicle-stimulating hormone on in vitro fertilization treatment outcome. Fertil Steril. 1997;67:889–899. doi: 10.1016/S0015-0282(97)81402-1.
    1. Westergaard LG, Erb K, Laursen S, Rasmussen PE, Rex S. The effect of human menopausal gonadotrophin and highly purified, urine-derived follicle stimulating hormone on the outcome of in-vitro fertilization in down-regulated normogonadotrophic women. Hum Reprod. 1996;11:1209–1213.
    1. Filicori M, Cognigni GE, Taraborrelli S, Spettoli D, Ciampaglia W, de Fatis CT, Pocognoli P. Luteinizing hormone activity supplementation enhances follicle-stimulating hormone efficacy and improves ovulation induction outcome. J Clin Endocrinol Metab. 1999;84:2659–2663. doi: 10.1210/jc.84.8.2659.
    1. Psychoyos A, (ed) The implantation window: basic and clinical aspects. Rome. 1993.
    1. Peng X, Kim JJ, Fazleabas AT. Apoptosis and Differentiation in Baboon Stromal Cells: A role for Chorionic Gonadotropin (CG)? Biol Reprod. 2000;62:307–308.
    1. Hyder SM, Stancel GM. Regulation of angiogenic growth factors in the female reproductive tract by estrogens and progestins. Mol Endocrinol. 1999;13:806–811. doi: 10.1210/me.13.6.806.
    1. Kilani Z, Dakkak A, Ghunaim S, Cognigni GE, Tabarelli C, Parmegiani L, Filicori M. A prospective, randomized, controlled trial comparing highly purified hMG with recombinant FSH in women undergoing ICSI: ovarian response and clinical outcomes. Hum Reprod. 2003;18:1194–1199. doi: 10.1093/humrep/deg252.
    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;108:1931–1938. doi: 10.1210/endo-108-5-1931.

Source: PubMed

3
구독하다