I read with great interest the systematic review of Gao & Jiang [1]  on the use of intrauterine hCG injection prior to embryo transfer in order to increase in vitro fertilization pregnancy rates. We were very excited about the possibility of resuming the use of this strategy, which until then was out of date due to previous systematic reviews showing inconsistent and conflicting result [2, 3].

I considered the Gao & Jiang study particularly interesting because it did the analysis of subgroups according to the dose of hCG used and the type of transfer, fresh or frozen, which is of great clinical relevance.

Regarding the time of intrauterine hCG application, the authors conclude that <15 minutes before transfer results in higher pregnancy rate than 6 hours and ≥48 hours. On this point, I have an issue. 

Considering that:

• The mechanism of action of hCG described by authors cited in the review would be to alter the expression of cytokines related to implantation, as well as to lead to extracellular matrix rupture and loss of tight-junction [4, 5];

• embryo implantation occurs approximately on the seventh day after fertilization;

I think that as important as the time interval between intrauterine hCG injection and the embryo transfer is the stage of the embryo at transfer, if cleavage or blastocyst, since this will determine the time interval between the two major biologic events: hCG injection signaling and embryo implantation.

From this, I would like to know if subgroup analysis could contemplate this variable (embryo stage at transfer)?

Oscar Duarte-Filho, M.D. 

References

[1] Gao M, Jiang X, Li B, Li L, Duan M, Zhang X, et al.: Intrauterine injection of human chorionic gonadotropin before embryo transfer can improve in vitro fertilization-embryo transfer outcomes: a meta-analysis of randomized controlled trials. Fertil Steril2019;112(1): 89-97.e81.

[2] Ye H, Hu J, He W, Zhang Y, Li C: The efficacy of intrauterine injection of human chorionic gonadotropin before embryo transfer in assisted reproductive cycles: Meta-analysis. J Int Med Res2015;43(6): 738-746.

[3] Osman A, Pundir J, Elsherbini M, Dave S, El-Toukhy T, Khalaf Y: The effect of intrauterine HCG injection on IVF outcome: a systematic review and meta-analysis. Reprod Biomed Online2016;33(3): 350-359.

[4] Tapia-Pizarro A, Argandoña F, Palomino WA, Devoto L: Human chorionic gonadotropin (hCG) modulation of TIMP1 secretion by human endometrial stromal cells facilitates extravillous trophoblast invasion in vitro. Hum Reprod2013;28(8): 2215-2227.

[5] Sacchi S, Sena P, Degli Esposti C, Lui J, La Marca A: Evidence for expression and functionality of FSH and LH/hCG receptors in human endometrium. J Assist Reprod Genet2018;35(9): 1703-1712.

I read with great interest the systematic review of Gao & Jiang [1]  on the use of intrauterine hCG injection prior to embryo transfer in order to increase in vitro fertilization pregnancy rates. We were very excited about the possibility of resuming the use of this strategy, which until then was out of date due to previous systematic reviews showing inconsistent and conflicting result [2, 3].

I considered the Gao & Jiang study particularly interesting because it did the analysis of subgroups according to the dose of hCG used and the type of transfer, fresh or frozen, which is of great clinical relevance.

Regarding the time of intrauterine hCG application, the authors conclude that <15 minutes before transfer results in higher pregnancy rate than 6 hours and ≥48 hours. On this point, I have an issue. 

Considering that:

• The mechanism of action of hCG described by authors cited in the review would be to alter the expression of cytokines related to implantation, as well as to lead to extracellular matrix rupture and loss of tight-junction [4, 5];

• embryo implantation occurs approximately on the seventh day after fertilization;

I think that as important as the time interval between intrauterine hCG injection and the embryo transfer is the stage of the embryo at transfer, if cleavage or blastocyst, since this will determine the time interval between the two major biologic events: hCG injection signaling and embryo implantation.

From this, I would like to know if subgroup analysis could contemplate this variable (embryo stage at transfer)?

Oscar Duarte-Filho, M.D. 

References

[1] Gao M, Jiang X, Li B, Li L, Duan M, Zhang X, et al.: Intrauterine injection of human chorionic gonadotropin before embryo transfer can improve in vitro fertilization-embryo transfer outcomes: a meta-analysis of randomized controlled trials. Fertil Steril2019;112(1): 89-97.e81.

[2] Ye H, Hu J, He W, Zhang Y, Li C: The efficacy of intrauterine injection of human chorionic gonadotropin before embryo transfer in assisted reproductive cycles: Meta-analysis. J Int Med Res2015;43(6): 738-746.

[3] Osman A, Pundir J, Elsherbini M, Dave S, El-Toukhy T, Khalaf Y: The effect of intrauterine HCG injection on IVF outcome: a systematic review and meta-analysis. Reprod Biomed Online2016;33(3): 350-359.

[4] Tapia-Pizarro A, Argandoña F, Palomino WA, Devoto L: Human chorionic gonadotropin (hCG) modulation of TIMP1 secretion by human endometrial stromal cells facilitates extravillous trophoblast invasion in vitro. Hum Reprod2013;28(8): 2215-2227.

[5] Sacchi S, Sena P, Degli Esposti C, Lui J, La Marca A: Evidence for expression and functionality of FSH and LH/hCG receptors in human endometrium. J Assist Reprod Genet2018;35(9): 1703-1712.