Clinical trial NCT03954587: What is the Optimal Cycle Regimen for Frozen- Thawed Embryo Transfer Cycles
Official title: What is the Optimal Cycle Regimen for Frozen- Thawed Embryo Transfer Cycles: Spontaneous Natural Cycles Versus Hormonal Replacement Treatment (HRT) Cycles
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Infertility
Female Infertility
Pregnancy Early
Keywords: Hormone replacement therapy
Frozen thawed embryos
Frozen embryo cycle
Lead sponsor: ART Fertility Clinics LLC
Sponsor class: OTHER
First posted: 2019-05-17
Enrollment: 4
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 42
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Female who underwent a previous ovarian stimulation for In Vitro Fertilisation/Intracytoplasmic Sperm Injection with pre-implantation genetic screening and embryo vitrification, who are planned for their first frozen thaw embryo transfer cycle

Brief summary: Investigators will be comparing artificial (HRT) frozen-thawed embryo transfer cycles to correctly conducted spontaneous natural cycles after the transfer of a chromosomally normal embryo.

Detailed description: The most common treatment protocols for frozen embryo transfers include natural cycles with or without human chorionic gonadotrophin (HCG) trigger or endometrial preparation with hormonal treatment (artificial cycles), with or without Gonadotrophin - releasing hormone agonist suppression. Recent studies comparing artificial and natural cycles concluded that the optimal means of endometrial preparation for frozen- thawed cycle remains unclear and both options may be offered to women with regular ovulatory cycles.

Correctly identified spontaneous natural cycles are the preferred option for frozen-thawed embryo transfer in women with regular menstrual cycles.

Investigators will be comparing artificial (HRT) frozen-thawed embryo transfer cycles to correctly conducted spontaneous natural cycles after the transfer of a chromosomally normal embryo.

Eligibility criteria: Inclusion criteria include the following:

1. Women aged 18 years to 42 years with regular menses (26-34 days)
2. Having 1 or 2 chromosomally normal cryopreserved blastocysts available for transfer.
3. First frozen-thawed transfer cycle
4. Progesterone level \< 1.5 ng/mL day of trigger injection in stimulation cycle from which embryos to be transferred were created.

Exclusion criteria include the following:

1. Polycystic ovarian syndrome
2. Poor ovarian responder in accordance with Bologna criteria
3. Uterine abnormality US / saline infusion sonohysterogram
4. Previous dilatation \& curettage (D\&C)
5. Hydrosalpinx
6. Asherman syndrome
7. History of endometriosis
8. ICSI due to severe male factor with testicular sperm
9. Any known contraindications or allergy to oral estradiol or progesterone.
10. Discontinuation of HRT medication ( medication error in research HRT cycle )
11. Failure to detect ovulation in the research natural cycle
12. Duration of estradiol exposure ≥ 17 days and endometrium \< 6mm
13. Spontaneous ovulation in HRT artificial cycle

Primary outcomes:
measure: Ongoing pregnancy rate to 8 weeks gestation
timeFrame: 8 weeks
measure: Pregnancy rate beta human chorionic gonadotropin (ß-hCG) > 5 IU
timeFrame: 12 days
measure: Biochemical pregnancy rate
timeFrame: 5 weeks
measure: Clinical implantation rate
timeFrame: 6 weeks
measure: Clinical pregnancy rate
timeFrame: 5 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Abu Dhabi
country: United Arab Emirates
facility: IVI Middle East Fertility Clinic
Study officials:
affiliation: IVI Middle East Fertility Clinic LLC
name: Carol Coughlan, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Roque M, Lattes K, Serra S, Sola I, Geber S, Carreras R, Checa MA. Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis. Fertil Steril. 2013 Jan;99(1):156-162. doi: 10.1016/j.fertnstert.2012.09.003. Epub 2012 Oct 3.
citation: Roque M, Valle M, Guimaraes F, Sampaio M, Geber S. Freeze-all policy: fresh vs. frozen-thawed embryo transfer. Fertil Steril. 2015 May;103(5):1190-3. doi: 10.1016/j.fertnstert.2015.01.045. Epub 2015 Mar 4.
citation: Bourgain C, Devroey P. The endometrium in stimulated cycles for IVF. Hum Reprod Update. 2003 Nov-Dec;9(6):515-22. doi: 10.1093/humupd/dmg045.
citation: Devroey P, Bourgain C, Macklon NS, Fauser BC. Reproductive biology and IVF: ovarian stimulation and endometrial receptivity. Trends Endocrinol Metab. 2004 Mar;15(2):84-90. doi: 10.1016/j.tem.2004.01.009.
citation: Kolibianakis E, Bourgain C, Albano C, Osmanagaoglu K, Smitz J, Van Steirteghem A, Devroey P. Effect of ovarian stimulation with recombinant follicle-stimulating hormone, gonadotropin releasing hormone antagonists, and human chorionic gonadotropin on endometrial maturation on the day of oocyte pick-up. Fertil Steril. 2002 Nov;78(5):1025-9. doi: 10.1016/s0015-0282(02)03323-x.
citation: Nikas G, Develioglu OH, Toner JP, Jones HW Jr. Endometrial pinopodes indicate a shift in the window of receptivity in IVF cycles. Hum Reprod. 1999 Mar;14(3):787-92. doi: 10.1093/humrep/14.3.787.
citation: Simon C, Garcia Velasco JJ, Valbuena D, Peinado JA, Moreno C, Remohi J, Pellicer A. Increasing uterine receptivity by decreasing estradiol levels during the preimplantation period in high responders with the use of a follicle-stimulating hormone step-down regimen. Fertil Steril. 1998 Aug;70(2):234-9. doi: 10.1016/s0015-0282(98)00140-x.
citation: Weinerman R, Mainigi M. Why we should transfer frozen instead of fresh embryos: the translational rationale. Fertil Steril. 2014 Jul;102(1):10-8. doi: 10.1016/j.fertnstert.2014.05.019. Epub 2014 Jun 2.
citation: Liu Y, Lee KF, Ng EH, Yeung WS, Ho PC. Gene expression profiling of human peri-implantation endometria between natural and stimulated cycles. Fertil Steril. 2008 Dec;90(6):2152-64. doi: 10.1016/j.fertnstert.2007.10.020. Epub 2008 Jan 14.
citation: Haouzi D, Assou S, Mahmoud K, Tondeur S, Reme T, Hedon B, De Vos J, Hamamah S. Gene expression profile of human endometrial receptivity: comparison between natural and stimulated cycles for the same patients. Hum Reprod. 2009 Jun;24(6):1436-45. doi: 10.1093/humrep/dep039. Epub 2009 Feb 26.
citation: Ghobara T, Gelbaya TA, Ayeleke RO. Cycle regimens for frozen-thawed embryo transfer. Cochrane Database Syst Rev. 2017 Jul 5;7(7):CD003414. doi: 10.1002/14651858.CD003414.pub3.
citation: Groenewoud ER, Cantineau AE, Kollen BJ, Macklon NS, Cohlen BJ. What is the optimal means of preparing the endometrium in frozen-thawed embryo transfer cycles? A systematic review and meta-analysis. Hum Reprod Update. 2013 Sep-Oct;19(5):458-70. doi: 10.1093/humupd/dmt030. Epub 2013 Jul 2.
citation: Groenewoud ER, Cohlen BJ, Macklon NS. Programming the endometrium for deferred transfer of cryopreserved embryos: hormone replacement versus modified natural cycles. Fertil Steril. 2018 May;109(5):768-774. doi: 10.1016/j.fertnstert.2018.02.135.
citation: Agha-Hosseini M, Hashemi L, Aleyasin A, Ghasemi M, Sarvi F, Shabani Nashtaei M, Khodarahmian M. Natural cycle versus artificial cycle in frozen-thawed embryo transfer: A randomized prospective trial. Turk J Obstet Gynecol. 2018 Mar;15(1):12-17. doi: 10.4274/tjod.47855. Epub 2018 Mar 29.
citation: Fatemi HM, Kyrou D, Bourgain C, Van den Abbeel E, Griesinger G, Devroey P. Cryopreserved-thawed human embryo transfer: spontaneous natural cycle is superior to human chorionic gonadotropin-induced natural cycle. Fertil Steril. 2010 Nov;94(6):2054-8. doi: 10.1016/j.fertnstert.2009.11.036. Epub 2010 Jan 25.
citation: Zimmermann G, Ackermann W, Alexander H. Epithelial human chorionic gonadotropin is expressed and produced in human secretory endometrium during the normal menstrual cycle. Biol Reprod. 2009 May;80(5):1053-65. doi: 10.1095/biolreprod.108.069575. Epub 2009 Jan 21.
citation: Shi Y, Sun Y, Hao C, Zhang H, Wei D, Zhang Y, Zhu Y, Deng X, Qi X, Li H, Ma X, Ren H, Wang Y, Zhang D, Wang B, Liu F, Wu Q, Wang Z, Bai H, Li Y, Zhou Y, Sun M, Liu H, Li J, Zhang L, Chen X, Zhang S, Sun X, Legro RS, Chen ZJ. Transfer of Fresh versus Frozen Embryos in Ovulatory Women. N Engl J Med. 2018 Jan 11;378(2):126-136. doi: 10.1056/NEJMoa1705334.
citation: O'Connor KA, Brindle E, Miller RC, Shofer JB, Ferrell RJ, Klein NA, Soules MR, Holman DJ, Mansfield PK, Wood JW. Ovulation detection methods for urinary hormones: precision, daily and intermittent sampling and a combined hierarchical method. Hum Reprod. 2006 Jun;21(6):1442-52. doi: 10.1093/humrep/dei497. Epub 2006 Jan 26.
citation: Irani M, Robles A, Gunnala V, Reichman D, Rosenwaks Z. Optimal parameters for determining the LH surge in natural cycle frozen-thawed embryo transfers. J Ovarian Res. 2017 Oct 16;10(1):70. doi: 10.1186/s13048-017-0367-7.