Administration of Human Chorionic Gonadotrophin Before Secretory Transformation of Frozen-thawed Embryo Transfer Cycles
Study Details
Study Description
Brief Summary
To investigate the role of parenteral hCG used for the transfer of cryopreserved- thawed embryos with HRT cycles in the outcome of artificially prepared FET cycles. Frozen-thawed embryo transfer (FET) cycles has increased recently contributing to about 30% of ART cycles,which improved pregnancy outcome from each oocyte retrieval.
Despite the extensive research in all areas of reproductive medicine and breakthroughs in ART to improve cycle outcome, the efficacy of embryo implantation is relatively low and continues to be the rate limiting factor. Successful embryo implantation is complicated process that requires synchrony between good-quality embryos and receptive endometrium. It is associated with the liberation and presence of various mediators secreted from both the developing embryo and the endometrium such as cyclic adenosine monophosphate (cAMP), relaxin, gonadotropin, prostaglandin E2 (PGE2), and glycoprotein. The achievement of optimal endometrial preparation in FET cycles is important not only for proper implantation but also for pregnancy outcome. However, no consensus on the optimal endometrial preparation protocol and various protocols are used in FET: modified natural, stimulated and artificial cycles, with the latter is the most commonly used. In artificial cycle, the endometrium is prepared by administration of exogenous oestrogen followed by progesterone to induce secretory transformation before embryo transfer (ET). Both hormones are essential for adequate endometrial preparation for implantation. Another key molecule that principally controls implantation is the human chorionic gonadotropin (hCG),which is one of the initial embryonic signals and the major embryoendometrial relationship regulator. It is expressed by blastocyst before the implantation, then increasingly produced the syncytiotrophoblast after implantation. The LH and hCG receptors are present in the human endometrium, via these receptors, local hCG has several paracrine effects at implantation site that modulate endometrial receptivity and finally lead to a stable implantation. It has been found to prolong the window of receptivity and enhance endometrial
angiogenesis through down regulation of insulin- like growth factor- binding protein 1 (IGFBP-1) and increasing vascular endothelial growth factor (VEGF), respectively. It also interferes with the biosynthesis of leukemia inhibitory factor and macrophage colony stimulating factor (LIF and M-CSF) both are involved in the embryo-maternal cross-talk and modulate trophoblast differentiation. In addition, hCG has been shown to have autocrine effects on the trophoblasts themselves, leading to increased differentiation and invasive potential, "hCG could well be a key regulator, triggering whether or not the embryo will implant". Although several studies investigated the role of intrauterine administration of hCG before embryo transfer on IVF outcome, this approach is not recommended yet and many reports are conflicting. On the other hand, because parenteral hCG is not usually used for the transfer of cryopreserved- thawed embryos with HRT cycles as ovulation is usually suppressed, there are few data about the benefit of hCG administration in the outcome of artificially prepared FET cycles.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
Study Design A randomized controlled trial will be conducted in IVF Center, Madina fertility center, Alexandria, Egypt, after approval by the Ethical Committee of Alexandria University. The study will be completely explained for all participants, and an informed consent form will be obtained. A total of 180 women will be allocated into two groups according to hCG administration before initiation of secretory phase transformation as performed by computerized randomization.In Group 1 (hCG): participants will receive endometrial preparation with estrogen and an intramuscular hCG injection will before progesterone supplementation, in Group 2 (control): participants will receive the conventional endometrial preparation with estrogen followed by progesterone supplementation.
Endometrial preparation The endometrial estrogen preparation process will be similar in both groups. All women will receive oral estradiol valerate 8 mg per day (4mg twice daily) from the day 2-3 of the menstrual cycle. Endometrial thickness will be measured by vaginal ultrasonography. From the 12th to 13th day of the cycle when endometrium reached the optimal thickness ≥8 mm, group 1 (hCG) will receive 10.000 IU hCG intramuscular injection in the morning then vaginal suppository progesterone 400 mg twice a day will be started in the afternoon. In group 2 (control) vaginal suppository progesterone 400 mg twice a day will be prescribed when endometrium reached the optimal thickness with no hCG administration. Those failed to reach the optimal endometrial thickness at day 12-13 of the cycle, the dose of EV will be increased to 12 mg per day. The FET will be cancelled if the endometrial thickness didn't reach to more than 7 mm in any group until 20th cycle day, ultimately.
Frozen-thawed embryo transfer Frozen-thawed embryo transfer will be done after synchronizing the day of progesterone treatment with the age of the embryo (only day 3 or day 5 good quality embryos will be transferred). Embryo thawing will be performed three to five days after progesterone supplementation according to the embryo stage at cryopreservation. Embryos will be transferred on the same day of thawing by a Labotect catheter. Both estradiol valerate and progesterone will be continued after the transfer in the same dosage of luteal support till the 12th week of gestational age if pregnancy occurred.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: HCG group n Group 1 (hCG): participants will receive endometrial preparation with estrogen and an intramuscular hCG injection will before progesterone supplementation |
Drug: Human Chorionic Gonadotrophin Intramuscular injection 10.000 IU
From the 12th to 13th day of the cycle when endometrium reached the optimal thickness ≥8 mm, group 1 (hCG) will receive 10.000 IU hCG intramuscular injection in the morning then vaginal suppository progesterone 400 mg twice a day will be started in the afternoon
|
| No Intervention: control group Group 2 (control): participants will receive the conventional endometrial preparation with estrogen followed by progesterone supplementation |
Outcome Measures
Primary Outcome Measures
- Clinical pregnancy: defined by observation of a gestational sac with embryonic fetal heart detected two weeks after positive β hCG. cycle [6 weeks gestatioal age .]
to calculate clinical pregnancy rate as percentage of cases who get clinical pregnancy to the total number of cases in each group .
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patient age ≤ 38 years.
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Normal 3D transvaginal ultrasound.
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At least two good quality embryos cryopreserved by vitrification.
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No GnRH agonists administration before FET cycle.
Exclusion Criteria
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Endometriosis.
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Uterine anomalies.
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Evidence of hydrosalpinx by hystrosalpingography or ultrasound.
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Evidence of immune disease, hematological or hormonal disorder.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Alexandria university | Alexandria | Egypt |
Sponsors and Collaborators
- Alexandria University
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
- Deng L, Chen X, Blockeel C, Ye DS, Chen SL. Intramuscular injection of human chorionic gonadotropin prior to secretory transformation in patients undergoing frozen-thawed embryo transfer cycles. Reprod Biol Endocrinol. 2020 May 25;18(1):52. doi: 10.1186/s12958-020-00606-y.
- Gao M, Jiang X, Li B, Li L, Duan M, Zhang X, Tian J, Qi K. 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 Steril. 2019 Jul;112(1):89-97.e1. doi: 10.1016/j.fertnstert.2019.02.027. Review.
- Laokirkkiat P, Thanaboonyawat I, Boonsuk S, Petyim S, Prechapanich J, Choavaratana R. Increased implantation rate after intrauterine infusion of a small volume of human chorionic gonadotropin at the time of embryo transfer: a randomized, double-blind controlled study. Arch Gynecol Obstet. 2019 Jan;299(1):267-275. doi: 10.1007/s00404-018-4962-7. Epub 2018 Nov 17.
- Licht P, Fluhr H, Neuwinger J, Wallwiener D, Wildt L. Is human chorionic gonadotropin directly involved in the regulation of human implantation? Mol Cell Endocrinol. 2007 Apr 15;269(1-2):85-92. Epub 2007 Feb 14. Review.
- Shiotani M, Matsumoto Y, Okamoto E, Yamada S, Mizusawa Y, Furuhashi K, Ogata H, Ogata S, Kokeguchi S. Is human chorionic gonadotropin supplementation beneficial for frozen and thawed embryo transfer in estrogen/progesterone replacement cycles?: A randomized clinical trial. Reprod Med Biol. 2017 Apr 4;16(2):166-169. doi: 10.1002/rmb2.12023. eCollection 2017 Apr.
- Tan H, Hu S; Qiongyu , Chen Y, Jin L, Wu C. The Effect of Intrauterine Administration of Human Chorionic Gonadotropin (hCG) Before Embryo Transfer During Assisted Reproductive Cycles: a Meta-Analysis of Randomized Controlled Trials. Geburtshilfe Frauenheilkd. 2019 Jul;79(7):713-722. doi: 10.1055/a-0837-3246. Epub 2019 Apr 1.
- Tesarik J, Hazout A, Mendoza C. Luteinizing hormone affects uterine receptivity independently of ovarian function. Reprod Biomed Online. 2003 Jul-Aug;7(1):59-64.
- HCG in FET cycles