Effect of hCG on Receptivity of the Human Endometrium

NCT01786252 | Completed Phase 4 Results

• 2 other identifiers: Endo-hCG-755IRB 12-755F
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

Worldwide, 1 in 12 couples experience difficulty in getting pregnant and seek the help of assisted reproductive technologies (ART) such as in vitro fertilization (IVF-egg is fertilized by sperm outside the body), ovarian stimulation (medications are used to stimulate egg development) and intra-cytoplasmic injection (ICSI-single sperm is injected directly into the egg). Regardless of the ART procedure being performed, the newly fertilized embryo must still implant into the mothers endometrium (inner lining of uterus). This implantation process in humans is surprisingly inefficient and accounts for up to 50% of ART failures. Intrauterine infusion of hCG prior to embryo transfer has recently been shown to increase pregnancy rates but the cellular mechanism for this increase is unknown. Successful implantation requires the newly fertilized embryo and the endometrium develop in a synchronized manner. This coordinated development is accomplished, in part, by proteins secreted by the embryo which circulate throughout the maternal bloodstream and alert the maternal body organs (i.e. ovary, endometrium, breast, ect) that fertilization has occurred. One of the earliest of these secreted proteins is human chorionic gonadotropin (hCG), which is the molecule detected in over-the-counter pregnancy tests. From previous studies, we know that hCG production by the embryo alerts the ovary to continue producing progesterone, a hormone required for pregnancy. However, very little is known about the direct effect of hCG on the endometrium during early pregnancy in humans. Using animal models, hCG has been shown to induce specific changes in the endometrium, suggesting that embryo-derived hCG may be "priming" the endometrium in anticipation of implantation. The goal of this research study is to examine the direct effect of hCG on the human endometrium and see if this "priming effect" is also present in humans. Findings from this research may reveal whether pre-treatment with hCG can enhance ART outcomes, especially pregnancy rates.

Conditions

Infertility; Subfertility

Keywords

embryo; implantation; blastocyst; in vitro fertilization; human chorionic gonadotropin

Outcome Measures

Primary Outcomes (4)

• Endometrial Staging in hCG Versus Vehicle Treated Patients

  All H\&E-stained endometrial biopsies were analyzed in a blinded manner for endometrial dating and glandular and stromal development. Criteria for endometrial dating included the presence or absence of sub-nuclear vacuoles, which is one of the more reproducible features of the Noyes dating criteria. For the purposes of statistical analysis, the most advanced elements in each of the two endometrial compartments were considered. Data are specifically reported as days post-ovulation induction.

  2 days following infusion of hCG or IVF media

• Expression of hCG Target NOTCH1 Protein by IHC in Endometrial Glands

  Staining intensity of each section was quantified by image analysis software ImageJ (NIH) resulting in a Digital Histology Score (D-HSCORE), ranging from 0 to 255. Higher scores are associated with stronger staining/expression, while lower scores are the opposite.

  2 days following infusion of hCG or IVF media

• Expression of hCG Target NOTCH1 Protein by IHC in Endometrial Stroma

  Staining intensity of each section was quantified by image analysis software ImageJ (NIH) resulting in a Digital Histology Score (D-HSCORE), ranging from 0 to 255. Higher scores are associated with stronger staining/expression, while lower scores are the opposite.

  2 days following infusion of hCG or IVF media

• Expression of hCG Target C3 Protein by IHC in Endometrial Stroma

  Staining intensity of each section was quantified by image analysis software ImageJ (NIH) resulting in a Digital Histology Score (D-HSCORE), ranging from 0 to 255. Higher scores are associated with stronger staining/expression, while lower scores are the opposite.

  2 days following infusion of hCG or IVF media

Study Arms (2)

Drug: human chorionic gonadotropin (hCG)

EXPERIMENTAL

Drug: human chorionic gonadotropin (hCG). A single intrauterine infusion of 500IU hCG dissolved in IVF media ("Global"-trademark) will be administered to participants in the experimental group three days after oocyte retrieval. Two days after this infusion, participant will return to clinic where a uterine lavage and an endometrial biopsy will be performed to obtain a sample of uterine secretory proteins and endometrial tissue, respectively, for research analysis.

Drug: human chorionic gonadotropin (hCG)

IVF media ("Global"-trademark)

PLACEBO COMPARATOR

Placebo Comparator for hCG. A single intrauterine infusion of IVF media without hCG will be administered to participants in the control group three days after oocyte retrieval. Two days after this infusion, participant will return to clinic and a sample of uterine secretory proteins and endometrial tissue, will be obtained via uterine lavage and endometrial biopsy, respectively, for research analysis.

Drug: Placebo Comparator (for hCG)

Interventions

human chorionic gonadotropin (hCG) DRUG

500IU of hCG diluted to a final volume of 50ul in IVF media ("Global"-trademark)

Also known as: Novarel, human chorionic gonadotropin

Drug: human chorionic gonadotropin (hCG)

Placebo Comparator (for hCG) DRUG

50ul of IVF medium ("Global"-trademark) to mimic hCG infusion

Also known as: IVF media, "Global" media-trademark

IVF media ("Global"-trademark)

Eligibility Criteria

• Age: 18 Years - 34 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• between the ages of 18-34 years old
• successfully applied for oocyte donor status at the Investigators Infertility clinic (The Fertility Center, 3230 Eagle Park Drive NE, suite 100. Grand Rapids MI 49525)
• meet the ASRM criteria for oocyte donation

You may not qualify if:

• younger than 18 years old or older than 34 years old
• have not successfully applied for oocyte donor status at the Investigators Infertility clinic (The Fertility Center, 3230 Eagle Park Drive NE, suite 100. Grand Rapids MI 49525)
• do not meet the ASRM criteria for oocyte donation

Sponsors & Collaborators

• Michigan State University: lead

Study Sites (1)

The Fertility Center , 3230 Eagle Park Drive NE, suite 100

Grand Rapids, Michigan, 49525, United States

Location

Related Publications (11)

• Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the 'black box' of early pregnancy loss. Hum Reprod Update. 2002 Jul-Aug;8(4):333-43. doi: 10.1093/humupd/8.4.333.

  PMID: 12206468 BACKGROUND

• Koot YE, Teklenburg G, Salker MS, Brosens JJ, Macklon NS. Molecular aspects of implantation failure. Biochim Biophys Acta. 2012 Dec;1822(12):1943-50. doi: 10.1016/j.bbadis.2012.05.017. Epub 2012 Jun 7.

  PMID: 22683339 BACKGROUND

• Fazleabas AT, Donnelly KM, Srinivasan S, Fortman JD, Miller JB. Modulation of the baboon (Papio anubis) uterine endometrium by chorionic gonadotrophin during the period of uterine receptivity. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2543-8. doi: 10.1073/pnas.96.5.2543.

  PMID: 10051679 BACKGROUND

• Banaszak S, Brudney A, Donnelly K, Chai D, Chwalisz K, Fazleabas AT. Modulation of the action of chorionic gonadotropin in the baboon (Papio anubis) uterus by a progesterone receptor antagonist (ZK 137. 316). Biol Reprod. 2000 Sep;63(3):820-5. doi: 10.1095/biolreprod63.3.820.

  PMID: 10952926 BACKGROUND

• Banerjee P, Sapru K, Strakova Z, Fazleabas AT. Chorionic gonadotropin regulates prostaglandin E synthase via a phosphatidylinositol 3-kinase-extracellular regulatory kinase pathway in a human endometrial epithelial cell line: implications for endometrial responses for embryo implantation. Endocrinology. 2009 Sep;150(9):4326-37. doi: 10.1210/en.2009-0394. Epub 2009 Jun 25.

  PMID: 19556419 BACKGROUND

• Sherwin JR, Sharkey AM, Cameo P, Mavrogianis PM, Catalano RD, Edassery S, Fazleabas AT. Identification of novel genes regulated by chorionic gonadotropin in baboon endometrium during the window of implantation. Endocrinology. 2007 Feb;148(2):618-26. doi: 10.1210/en.2006-0832. Epub 2006 Nov 16.

  PMID: 17110430 BACKGROUND

• Sherwin JR, Hastings JM, Jackson KS, Mavrogianis PA, Sharkey AM, Fazleabas AT. The endometrial response to chorionic gonadotropin is blunted in a baboon model of endometriosis. Endocrinology. 2010 Oct;151(10):4982-93. doi: 10.1210/en.2010-0275. Epub 2010 Jul 28.

  PMID: 20668030 BACKGROUND

• Brosens JJ, Hodgetts A, Feroze-Zaidi F, Sherwin JR, Fusi L, Salker MS, Higham J, Rose GL, Kajihara T, Young SL, Lessey BA, Henriet P, Langford PR, Fazleabas AT. Proteomic analysis of endometrium from fertile and infertile patients suggests a role for apolipoprotein A-I in embryo implantation failure and endometriosis. Mol Hum Reprod. 2010 Apr;16(4):273-85. doi: 10.1093/molehr/gap108. Epub 2009 Dec 14.

  PMID: 20008415 BACKGROUND

• Evans J, Catalano RD, Brown P, Sherwin R, Critchley HO, Fazleabas AT, Jabbour HN. Prokineticin 1 mediates fetal-maternal dialogue regulating endometrial leukemia inhibitory factor. FASEB J. 2009 Jul;23(7):2165-75. doi: 10.1096/fj.08-124495. Epub 2009 Mar 2.

  PMID: 19255255 BACKGROUND

• Mansour R, Tawab N, Kamal O, El-Faissal Y, Serour A, Aboulghar M, Serour G. Intrauterine injection of human chorionic gonadotropin before embryo transfer significantly improves the implantation and pregnancy rates in in vitro fertilization/intracytoplasmic sperm injection: a prospective randomized study. Fertil Steril. 2011 Dec;96(6):1370-1374.e1. doi: 10.1016/j.fertnstert.2011.09.044. Epub 2011 Nov 1.

  PMID: 22047664 BACKGROUND

• Strug MR, Su R, Young JE, Dodds WG, Shavell VI, Diaz-Gimeno P, Ruiz-Alonso M, Simon C, Lessey BA, Leach RE, Fazleabas AT. Intrauterine human chorionic gonadotropin infusion in oocyte donors promotes endometrial synchrony and induction of early decidual markers for stromal survival: a randomized clinical trial. Hum Reprod. 2016 Jul;31(7):1552-61. doi: 10.1093/humrep/dew080. Epub 2016 Apr 26.

  PMID: 27122490 DERIVED

MeSH Terms

Conditions

Infertility

Interventions

Chorionic Gonadotropin

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Gonadotropins; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Placental Hormones; Peptides; Amino Acids, Peptides, and Proteins; Pregnancy Proteins; Proteins

Results Point of Contact

• Title: Dr. Asgerally Fazleabas
• Organization: Michigan State University

asgi@hc.msu.edu

(517) 884-6031

Study Officials

• Asgerally T. Fazleabas, PhD

  Michigan State University. Assistant Chair-Dept of Obstetrics, Gynecology&Reproductive Biology

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor and Associate Chair, Department of Obstetrics,Gynecology+Reproductive Biology

Study Record Dates

• First Submitted: February 5, 2013
• First Posted: February 7, 2013
• Study Start: January 1, 2013
• Primary Completion: March 1, 2016
• Study Completion: March 1, 2016
• Last Updated: February 24, 2017
• Results First Posted: November 1, 2016

Record last verified: 2017-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)