Intrauterine human chorionic gonadotropin infusion in oocyte donors promotes endometrial synchrony and induction of early decidual markers for stromal survival: a randomized clinical trial.
Does a single intrauterine infusion of human chorionic gonadotropin (hCG) at the time corresponding to a Day 3 embryo transfer in oocyte donors induce favorable molecular changes in the endometrium for embryo implantation?



Intrauterine hCG was associated with endometrial synchronization between endometrial glands and stroma following ovarian stimulation and the induction of early decidual markers associated with stromal cell survival.



The clinical potential for increasing IVF success rates using an intrauterine hCG infusion prior to embryo transfer remains unclear based on previously reported positive and non-significant findings. However, infusion of CG in the non-human primate increases the expression of pro-survival early decidual markers important for endometrial receptivity, including α-smooth muscle actin (α-SMA) and NOTCH1.



Oocyte donors (n=15) were randomly assigned to receive an intrauterine infusion of 500 IU hCG (n=7) or embryo culture media vehicle (n=8) 3 days following oocyte retrieval during their donor stimulation cycle. Endometrial biopsies were performed 2 days later, followed by either RNA isolation or tissue fixation in formalin and paraffin embedding.



Reverse transcription of total RNA from endometrial biopsies generated cDNA, which was used for analysis in the endometrial receptivity array (ERA; n = 5/group) or quantitative RT-PCR to determine relative expression of ESR1, PGR, C3 and NOTCH1. Tissue sections were stained with hematoxylin and eosin followed by blinded staging analysis for dating of endometrial glands and stroma. Immunostaining for ESR1, PGR, α-SMA, C3 and NOTCH1 was performed to determine their tissue localization.



Intrauterine hCG infusion was associated with endometrial synchrony and reprograming of stromal development following ovarian stimulation. ESR1 and PGR were significantly elevated in the endometrium of hCG-treated patients, consistent with earlier staging. The ERA did not predict an overall positive impact of intrauterine hCG on endometrial receptivity. However, ACTA2, encoding α-SMA was significantly increased in response to intrauterine hCG. Similar to the hCG-treated non-human primate, sub-epithelial and peri-vascular α-SMA expression was induced in women following hCG infusion. Other known targets of hCG in the baboon were also found to be increased, including C3 and NOTCH1, which have known roles in endometrial receptivity.



This study differs from our previous work in the hCG-treated non-human primate along with clinical studies in infertile patients. Specifically, we performed a single intrauterine infusion in oocyte donors instead of either continuous hCG via an osmotic mini-pump in the baboon or infusion followed by blastocyst-derived hCG in infertile women undergoing embryo transfer. Therefore, the full impact of intrauterine hCG in promoting endometrial receptivity may not have been evident.



Our findings suggest a potential clinical benefit for intrauterine hCG prior to embryo transfer on Day 3 in counteracting endometrial dyssynchrony from ovarian stimulation and promoting expression of markers important for stromal survival. Finally, there were no obvious negative effects of intrauterine hCG treatment.



Funding for this work was provided by NICHD R01 HD042280 (A.T.F.) and NICHD F30 HD082951 (M.R.S.). C.S. and P.D.-G are co-inventors of the patented ERA, which is owned by IGENOMIX SL and was used in this study, and C.S. is a shareholder in IGENOMIX SL. M.R.-A. is employed by IGENOMIX SL. No other authors have any conflicts of interest to report.



This study was registered with ClinicalTrials.gov (NCT01786252).



5 February 2013.



10 May 2013.
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, MI, USA.
Michael R
MR
Strug
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, MI, USA.
Renwei
R
Su
The Fertility Center, Grand Rapids, MI, USA.
James E
JE
Young
The Fertility Center, Grand Rapids, MI, USA.
William G
WG
Dodds
The Fertility Center, Grand Rapids, MI, USA.
Valerie I
VI
Shavell
Fundación Instituto Valenciano de Infertilidad (FIVI), Department of Obstetrics and Gynecology, School of Medicine, Valencia University and Instituto Universitario IVI/INCLIVA, Valencia, Spain.
Patricia
P
Díaz-Gimeno
Fundación Instituto Valenciano de Infertilidad (FIVI), Department of Obstetrics and Gynecology, School of Medicine, Valencia University and Instituto Universitario IVI/INCLIVA, Valencia, Spain.
Maria
M
Ruíz-Alonso
Fundación Instituto Valenciano de Infertilidad (FIVI), Department of Obstetrics and Gynecology, School of Medicine, Valencia University and Instituto Universitario IVI/INCLIVA, Valencia, Spain.
Carlos
C
Simón
Department of Obstetrics and Gynecology, Greenville Health System, Greenville, SC, USA.
Bruce A
BA
Lessey
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, MI, USA The Fertility Center, Grand Rapids, MI, USA.
Richard E
RE
Leach
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, MI, USA asgi@hc.msu.edu.
Asgerally T
AT
Fazleabas
D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000008:administration & dosage / Q000494:pharmacology*; D003656:Decidua / Q000378:metabolism; D004624:Embryo Transfer / Q000379:methods; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D008954:Models, Biological; D054315:Oocyte Retrieval; D012313:RNA / Q000378:metabolism; D012102:Reproductive Control Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D014019:Tissue Donors
D015415:Biomarkers; D006063:Chorionic Gonadotropin; D012102:Reproductive Control Agents; D012313:RNA
Notch; complement; controlled ovarian stimulation; decidualization; embryo implantation; endometrial receptivity; endometrium; hCG; oocyte donors