Effect of hCG on Receptivity of the Human Endometrium

Infertility Clinical Trial

Official title:

The Effect of hCG on the Human Endometrium

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01786252
• Other study ID #: Endo-hCG-755
• Secondary ID: IRB 12-755F
• Status: Active, not recruiting
• Phase: Phase 4
• First received: February 5, 2013
• Last updated: March 8, 2015
• Start date: January 2013
• Est. completion date: January 2017

Study information

• Verified date: March 2015
• Source: Michigan State University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 30
• Est. completion date: January 2017
• Est. primary completion date: January 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 34 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Infertility
• Subfertility

Intervention

Drug:
• human chorionic gonadotropin (hCG)
500IU of hCG diluted to a final volume of 50ul in IVF media ("Global"-trademark)
• Placebo Comparator (for hCG)
50ul of IVF medium ("Global"-trademark) to mimic hCG infusion

Locations

Country	Name	City	State
United States	The Fertility Center , 3230 Eagle Park Drive NE, suite 100	Grand Rapids	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Michigan State University

Country where clinical trial is conducted

United States, 

References & Publications (10)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. Epub 2006 Nov 16. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Evaluate the effect of hCG on endometrial morphology	Participants in the experimental group will receive a single intrauterine infusion of hCG (500IU) diluted in IVF media three days after oocyte retrieval. Participants in the control group will receive a single intrauterine infusion of IVF media only. Two days after this infusion, both experimental and control participants will return to the clinic where a sample of endometrial tissue will be obtained via pipelle biopsy. Histochemical and immunochemical analysis will be used to evaluate the effect of hCG on endometrial morphology.	within three years of study completion	No
Primary	Evaluate the effect of hCG on endometrial gene and protein expression levels	Participants in the experimental group will receive a single intrauterine infusion of hCG (500IU) diluted in IVF media three days after oocyte retrieval. Participants in the control group will receive a single intrauterine infusion of IVF media only. Two days after this infusion, both experimental and control participants will return to the clinic where a sample of endometrial tissue will be obtained via pipelle biopsy. Cellular and molecular analysis will be used to evaluate the effect of hCG on endometrial gene and protein expression levels.	within three years of study completion	No
Secondary	Evaluate the effect of hCG on endometrial secretory proteins.	Participants in the experimental group will receive a single intrauterine infusion of hCG (500IU) diluted in IVF media three days after oocyte retrieval. Participants in the control group will receive a single intrauterine infusion of IVF media only. Two days after this infusion, both experimental and control participants will return to the clinic where a sample of uterine secretory proteins will be obtained via uterine lavage with sterile saline. ELISA/Proteomic analysis will be used to evaluate the effect of hCG on uterine secretory proteins.	within three years of study completion	No