Low-Dose Human Chorionic Gonadotropin Adjunct to an Antagonist Protocol in Assisted Reproductive Technology: a Randomized Trial Study

  • Marzieh Aghahosseini Department of Infertility, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
  • Ashraf Aleyasin Department of Infertility, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
  • Habibeh Yekehtaz Department of Infertility, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
  • Ladan Kashani Mail Department of Infertility, Arash Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Low-dose hCG, GnRH antagonist, Ovarian stimulation, Recombinant FSH, Luteinizing hormone


The aim of this study was to evaluate the outcomes of adding low-dose hCG (human chorionic gonadotropin), as an LH active supplement, to a GnRH antagonist protocol in patients undergoing assisted reproduction techniques. In this parallel-group randomized clinical trial, 137 infertile female outpatients aged 20 - 39 years were randomized into two groups: hCG group and non-hCG group. All patients received r-FSH (150-300 IU) and then a GnRH-antagonist, Cetrorelix (0.25 mg/day). Concomitantly with Cetrorelix, patients in the hCG group received low-dose hCG (200 IU daily), but the patients in the non-hCG group did not. 10,000 IU Urinary hCG (10,000 IU) was injected to all patients, and ICSI was performed after oocyte retrieval. The primary outcome of this study was comparing the pregnancy rates between two study groups. Other differences between two groups such as serum estradiol concentration, fertilization rate, etc. were considered as secondary outcomes. A total of 130 patients completed this trial. No significant difference was detected between pregnancy rates of the two groups (P=0.52) as well as the fertilization, implantation and ongoing pregnancy rates (P=0.11, P=0.75 and P=0.06 respectively). The only significant difference between two groups was a higher concentration of estradiol in the hCG-treated patients (P<0.05). HCG-treated patients experienced a shorter treatment duration and a lower r-FSH required dose than the non-hCG group, but none of these differences were statistically significant (P=0.19 and P=0.10, respectively). The findings of the current study did not support advantages of adding low-dose hCG to GnRH antagonist plus r-FSH protocol in an unselected population of patients. Well-designed trials with a larger sample size for specific patients' subgroups are warranted.


Lenton EA, Woodward B. Natural-cycle versus stimulatedcycle IVF: is there a role for IVF in the natural cycle? J Assist Reprod Genet 1993;10(6):406-8.

Jennings JC, Moreland K, Peterson CM. In vitro fertilisation. A review of drug therapy and clinical management. Drugs 1996;52(3):313-43.

Al-In any HG, Abou-Setta AM, Aboulghar M. Gonadotrophin-releasing hormone antagonists for assisted conception. Cochrane Database Syst Rev 2006(3):CD001750.

Marci R, Caserta D, Lisi F, et al. In vitro fertilization stimulation protocol for normal responder patients. Gynecol Endocrinol 2013;29(2):109-12.

Depalo R, Jayakrishan K, Garruti G, et al. GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer (IVF/ET). Reprod Biol Endocrinol 2012;10(1):26.

Griesinger G. Ovarian hyperstimulation syndrome prevention strategies: use of gonadotropin-releasing hormone antagonists. Semin Reprod Med 2010;28(6):493-9.

Olivennes F, Cunha-Filho JS, Fanchin R, et al. The use of GnRH antagonists in ovarian stimulation. Hum Reprod Update 2002;8(3):279-90.

Tarlatzis BC, Kolibianakis EM. GnRH agonists vs antagonists. Best Pract Res Clin Obstet Gynaecol 2007;21(1):57-65.

Huirne JA, Homburg R, Lambalk CB. Are GnRH antagonists comparable to agonists for use in IVF? Hum Reprod 2007;22(11):2805-13.

Ragni G, Vegetti W, Riccaboni A, et al. Comparison of GnRH agonists and antagonists in assisted reproduction cycles of patients at high risk of ovarian hyperstimulation syndrome. Hum Reprod 2005;20(9):2421-5.

Ditkoff EC, Cassidenti DL, Paulson RJ, et al. The gonadotropin-releasing hormone antagonist (Nal-Glu) acutely blocks the luteinizing hormone surge but allows for resumption of folliculogenesis in normal women. Am J Obstet Gynecol 1991;165(6 Pt 1):1811-7.

Albano C, Smitz J, Camus M, et al. Hormonal profile during the follicular phase in cycles stimulated with a combination of human menopausal gonadotrophin and gonadotrophin-releasing hormone antagonist (Cetrorelix). Hum Reprod 1996;11(10):2114-8.

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(5):1003-8.

Griesinger G, Dawson A, Schultze-Mosgau A, et al. Assessment of luteinizing hormone level in the gonadotropin-releasing hormone antagonist protocol. Fertil Steril. 2006;85(3):791-3.

Shoham Z. The clinical therapeutic window for luteinizing hormone in controlled ovarian stimulation. Fertil Steril 2002;77(6):1170-7.

Weghofer A, Schnepf S, Barad D, et al. The impact of luteinizing hormone in assisted reproduction: a review. Curr Opin Obstet Gynecol 2007;19(3):253-7.

Filicori M, Cognigni GE, Taraborrelli S, et al. Luteinizing hormone activity supplementation enhances folliclestimulating hormone efficacy and improves ovulation induction outcome. J Clin Endocrinol Metab 1999;84(8):2659-63.

Acevedo B, Sanchez M, Gomez JL, et al. Luteinizing hormone supplementation increases pregnancy rates in gonadotropin-releasing hormone antagonist donor cycles. Fertil Steril 2004;82(2):343-7.

Gordon UD, Harrison RF, Fawzy M, et al. A randomized prospective assessor-blind evaluation of luteinizing hormone dosage and in vitro fertilization outcome. Fertil Steril 2001;75(2):324-31.

Serafini P, Yadid I, Motta EL, et al. 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(4):830-8.

Cedrin-Durnerin I, Grange-Dujardin D, Laffy A, 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.

Kosmas IP, Zikopoulos K, Georgiou I, et al. Low-dose HCG may improve pregnancy rates and lower OHSS in antagonist cycles: a meta-analysis. Reprod Biomed Online 2009;19(5):619-30.

Koichi K, Yukiko N, Shima K, et al. Efficacy of low-dose human chorionic gonadotropin (hCG) in a GnRH antagonist protocol. J Assist Reprod Genet 2006;23(5):223-8.

Beretsos P, Partsinevelos GA, Arabatzi E, et al. "hCG priming" effect in controlled ovarian stimulation through a long protocol. Reprod Biol Endocrinol 2009;7(8):91.

Propst AM, Hill MJ, Bates GW, et al. 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.

Van Horne AK, Bates GW Jr, Robinson RD, et al. Recombinant follicle-stimulating hormone (rFSH) supplemented with low-dose human chorionic gonadotropin compared with rFSH alone for ovarian stimulation for in vitro fertilization. Fertil Steril 2007;88(4):1010-3.

da Silva AL, Arbo E, Fanchin R. Early versus late hCG administration to trigger ovulation in mild stimulated IUI cycles: a randomized clinical trial. Eur J Obstet Gynecol Reprod Biol 2012;164(2):156-60.

Orvieto R. Timing of human chorionic gonadotropin trigger, in patients undergoing controlled ovarian hyperstimulation for IVF, using the GnRH antagonist protocol. Hum Fertil (Camb) 2012;15(4):221.

Stenman UH, Tiitinen A, Alfthan H, et al. The classification, functions and clinical use of different isoforms of HCG. Hum Reprod Update 2006;12(6):769-84.

Gomaa H, Casper RF, Esfandiari N, et al. Addition of low dose hCG to rFSh benefits older women during ovarian stimulation for IVF. Reprod Biol Endocrinol 2012;10(8):55.

Filicori M, Cognigni GE, Taraborrelli S, et al. Intracytoplasmic sperm injection pregnancy after low-dose human chorionic gonadotropin alone to support ovarian folliculogenesis. Fertil Steril 2002;78(2):414-6.

Levi-Setti PE, Cavagna M, Bulletti C. Recombinant gonadotrophins associated with GnRH antagonist (cetrorelix) in ovarian stimulation for ICSI: comparison of r-FSH alone and in combination with r-LH. Eur J Obstet Gynecol Reprod Biol 2006;126(2):212-6.

Tarlatzis B, Tavmergen E, Szamatowicz M, et al. The use of recombinant human LH (lutropin alfa) in the late stimulation phase of assisted reproduction cycles: a double-blind, randomized, prospective study. Hum Reprod 2006;21(1):90-4.

Lisi F, Rinaldi L, Fishel S, et al. Evaluation of two doses of recombinant luteinizing hormone supplementation in an unselected group of women undergoing follicular stimulation for in vitro fertilization. Fertil Steril 2005;83(2):309-15.

Lahoud R, Al-Jefout M, Tyler J, et al. A relative reduction in mid-follicular LH concentrations during GnRH agonist IVF/ICSI cycles leads to lower live birth rates. Hum Reprod 2006;21(10):2645-9.

O'Dea L, O'Brien F, Currie K, et al. Follicular development induced by recombinant luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in anovulatory women with LH and FSH deficiency: evidence of a threshold effect. Curr Med Res Opin 2008;24(10):2785-93.

McDonough PG. Stimulation protocols-floors and ceilings for LH activity. Fertil Steril 2003;79(6):1473-4.

Shoham Z, Smith H, Yeko T, et al. Recombinant LH (lutropin alfa) for the treatment of hypogonadotrophic women with profound LH deficiency: a randomized, double-blind, placebo-controlled, proof-of-efficacy study. Clin Endocrinol (Oxf) 2008;69(3):471-8.

Kaufmann R, Dunn R, Vaughn T, et al. Recombinant human luteinizing hormone, lutropin alfa, for the induction of follicular development and pregnancy in profoundly gonadotrophin-deficient women. Clin Endocrinol (Oxf) 2007;67(4):563-9.

Recombinant human luteinizing hormone (LH) to support recombinant human follicle-stimulating hormone (FSH)- induced follicular development in LH- and FSH-deficient anovulatory women: a dose-finding study. The European Recombinant Human LH Study Group. J Clin Endocrinol Metab 1998;83(5):1507-14.

Crowley WF, Jr., McArthur JW. Simulation of the normal menstrual cycle in Kallman's syndrome by pulsatile administration of luteinizing hormone-releasing hormone (LHRH). J Clin Endocrinol Metab 1980;51(1):173-5.

Bosch E, Vidal C, Labarta E, et al. Highly purified hMG versus recombinant FSH in ovarian hyperstimulation with GnRH antagonists--a randomized study. Hum Reprod 2008;23(10):2346-51.

Zafeiriou S, Loutradis D, Michalas S. The role of gonadotropins in follicular development and their use in ovulation induction protocols for assisted reproduction. Eur J Contracept Reprod Health Care 2000;5(2):157-67.

Rice VC, Zusmanis K, Malter H, et al. Pure FSH alone induces ovulation and subsequent pregnancy in the mouse resulting in fetal development. Life Sci 1993;53(1):31-9.

Chappel SC, Howles C. Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Hum Reprod 1991;6(9):1206-12.

Levy DP, Navarro JM, Schattman GL, Det al. The role of LH in ovarian stimulation: exogenous LH: let's design the future. Hum Reprod 2000;15(11):2258-65.

Cole LA. Biological functions of hCG and hCG-related molecules. Reprod Biol Endocrinol 2010;8(1):102.

Jutisz M, Tertrin-Clary C. Luteinizing hormone and human chorionic gonadotropin: structure and activity. Curr Top Exp Endocrinol 1974;2(6):195-246.

Galet C, Ascoli M. The differential binding affinities of the luteinizing hormone (LH)/choriogonadotropin receptor for LH and choriogonadotropin are dictated by different extracellular domain residues. Mol Endocrinol 2005;19(5):1263-76.

Yamoto M, Shima K, Nakano R. Gonadotropin receptors in human ovarian follicles and corpora lutea throughout the menstrual cycle. Horm Res 1992;37(Suppl 1):5-11.

Richards JS, Jahnsen T, Hedin L, et al. Ovarian follicular development: from physiology to molecular biology. Recent Prog Horm Res 1987;43:231-76.

Filicori M, Cognigni GE, Gamberini E, et al. Efficacy of low-dose human chorionic gonadotropin alone to complete controlled ovarian stimulation. Fertil Steril 2005;84(2):394-401.

Madani T, Mohammadi Yeganeh L, Khodabakhshi S, et al. Efficacy of low dose hCG on oocyte maturity for ovarian stimulation in poor responder women undergoing intracytoplasmic sperm injection cycle: a randomized controlled trial. J Assist Reprod Genet 2012;29(11):1213-20.

Jaakkola T, Ding YQ, Kellokumpu-Lehtinen P, et al. The ratios of serum bioactive/immunoreactive luteinizing hormone and follicle-stimulating hormone in various clinical conditions with increased and decreased gonadotropin secretion: reevaluation by a highly sensitive immunometric assay. J Clin Endocrinol Metab 1990;70(6):1496-505.

Rosenfield RL, Helke J. Is an immunoassay available for the measurement of bioactive LH in serum? J Androl 1992;13(1):1-10.

Shoham Z, Jacobs HS, Insler V. Luteinizing hormone: its role, mechanism of action, and detrimental effects when hypersecreted during the follicular phase. Fertil Steril 1993;59(6):1153-61.

Dunger DB, Villa AK, Matthews DR, et al. Pattern of secretion of bioactive and immunoreactive gonadotrophins in normal pubertal children. Clin Endocrinol (Oxf) 1991;35(3):267-75.

How to Cite
Aghahosseini M, Aleyasin A, Yekehtaz H, Kashani L. Low-Dose Human Chorionic Gonadotropin Adjunct to an Antagonist Protocol in Assisted Reproductive Technology: a Randomized Trial Study. Acta Med Iran. 52(6):430-437.