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Effect of hCG on Receptivity of the Human Endometrium

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ClinicalTrials.gov Identifier: NCT01786252
Recruitment Status : Completed
First Posted : February 7, 2013
Results First Posted : November 1, 2016
Last Update Posted : February 24, 2017
Sponsor:
Information provided by (Responsible Party):
Asgerally Fazleabas, Michigan State University

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.


Condition or disease Intervention/treatment Phase
Infertility Subfertility Drug: human chorionic gonadotropin (hCG) Drug: Placebo Comparator (for hCG) Phase 4

Detailed Description:

Embryo implantation in humans is surprisingly inefficient and represents a major limiting factor for enhancement of ART success rates (ref 1-2). Successful implantation requires synchronized development between the newly fertilized embryo and the maternal endometrium within a specific window of time. In mammals, this coordinated development is accomplished, in part, by embryonic secretions which alert the body that fertilization has occurred.

One of the earliest proteins produced by the embryo is human chorionic gonadotropin (hCG). Previous research has shown that hCG maintains progesterone production by the ovary, a hormone required for the maintenance of pregnancy. However, very little is known about the direct effect of hCG on the human endometrium. Our laboratory has previously shown that intrauterine infusion of hCG in the non-human primate can induce endometrial changes that mimic the initial stages of early pregnancy (i.e. altered cellular morphology, pre-decidual response and increased glandular activity; ref 3-4). These results suggest that embryo-derived hCG may also act directly upon the endometrium to "prime" it in anticipation of implantation. Research from other labs examining the effect of hCG on endometrial genes in vitro support this hypothesis (ref: 5-9). Additionally, a recent study of women undergoing ART revealed significantly increased implantation and pregnancy rates when the embryo transfer was preceded by intra-uterine infusion of 500IU hCG (ref 10).

The purpose of this study is to determine whether the endometrial response to hCG seen previously in our non-human primate model is also present in women and to characterize this effect. Women who plan to undergo controlled ovarian stimulation for the purpose of egg donation will be eligible to participate in this research. Subjects in experimental group will receive a single intrauterine infusion of hCG (500IU) diluted in IVF media 3 days after oocyte retrieval. Control subjects will receive a single intrauterine infusion of IVF media only. Two days after infusion, both experimental group and control participants will return to the clinic where a sample of endometrial tissue will be obtained via pipelle biopsy and a sample of uterine secretory proteins will be obtained via uterine lavage. The uterine lavage samples will be examined using ELISA/proteomic analysis to determine the effect of hCG on uterine protein secretions. One portion of the endometrial biopsy will be formalin-fixed and paraffin-embedded for analysis of morphological and structural changes following hCG exposure. The second portion will be used for cellular and molecular analysis to determine the effect of hCG on genes and proteins of interest.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: The Effect of hCG on the Human Endometrium
Study Start Date : January 2013
Actual Primary Completion Date : March 2016
Actual Study Completion Date : March 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Drug: human chorionic gonadotropin (hCG)
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)
500IU of hCG diluted to a final volume of 50ul in IVF media ("Global"-trademark)
Other Name: Novarel, human chorionic gonadotropin

Placebo Comparator: IVF media ("Global"-trademark)
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)
50ul of IVF medium ("Global"-trademark) to mimic hCG infusion
Other Names:
  • IVF media
  • "Global" media-trademark




Primary Outcome Measures :
  1. Endometrial Staging in hCG Versus Vehicle Treated Patients [ Time Frame: 2 days following infusion of hCG or IVF media ]
    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. Expression of hCG Target NOTCH1 Protein by IHC in Endometrial Glands [ Time Frame: 2 days following infusion of hCG or IVF media ]
    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.

  3. Expression of hCG Target NOTCH1 Protein by IHC in Endometrial Stroma [ Time Frame: 2 days following infusion of hCG or IVF media ]
    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.

  4. Expression of hCG Target C3 Protein by IHC in Endometrial Stroma [ Time Frame: 2 days following infusion of hCG or IVF media ]
    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.



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Ages Eligible for Study:   18 Years to 34 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. between the ages of 18-34 years old
  2. 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)
  3. meet the ASRM criteria for oocyte donation

Exclusion Criteria:

  1. younger than 18 years old or older than 34 years old
  2. 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)
  3. do not meet the ASRM criteria for oocyte donation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01786252


Locations
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United States, Michigan
The Fertility Center , 3230 Eagle Park Drive NE, suite 100
Grand Rapids, Michigan, United States, 49525
Sponsors and Collaborators
Michigan State University
Investigators
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Principal Investigator: Asgerally T. Fazleabas, PhD Michigan State University. Assistant Chair-Dept of Obstetrics, Gynecology&Reproductive Biology

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Asgerally Fazleabas, Professor and Associate Chair, Department of Obstetrics,Gynecology+Reproductive Biology, Michigan State University
ClinicalTrials.gov Identifier: NCT01786252     History of Changes
Other Study ID Numbers: Endo-hCG-755
IRB 12-755F ( Other Identifier: MSU )
First Posted: February 7, 2013    Key Record Dates
Results First Posted: November 1, 2016
Last Update Posted: February 24, 2017
Last Verified: January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Asgerally Fazleabas, Michigan State University:
embryo
implantation
blastocyst
in vitro fertilization
human chorionic gonadotropin
Additional relevant MeSH terms:
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Infertility
Genital Diseases, Male
Genital Diseases, Female
Chorionic Gonadotropin
Reproductive Control Agents
Physiological Effects of Drugs