Clinical trial NCT01786252: Effect of hCG on Receptivity of the Human Endometrium
Official title: The Effect of hCG on the Human Endometrium
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Infertility
Subfertility
Keywords: embryo
implantation
blastocyst
in vitro fertilization
human chorionic gonadotropin
Lead sponsor: Michigan State University
Sponsor class: OTHER
First posted: 2013-02-07
Enrollment: 15
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 34
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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

Primary outcomes:
measure: Endometrial Staging in hCG Versus Vehicle Treated Patients
timeFrame: 2 days following infusion of hCG or IVF media
measure: Expression of hCG Target NOTCH1 Protein by IHC in Endometrial Glands
timeFrame: 2 days following infusion of hCG or IVF media
measure: Expression of hCG Target NOTCH1 Protein by IHC in Endometrial Stroma
timeFrame: 2 days following infusion of hCG or IVF media
measure: Expression of hCG Target C3 Protein by IHC in Endometrial Stroma
timeFrame: 2 days following infusion of hCG or IVF media
Secondary outcomes:
Other outcomes:
Locations:
city: Grand Rapids
country: United States
facility: The Fertility Center , 3230 Eagle Park Drive NE, suite 100
state: Michigan
Study officials:
affiliation: Michigan State University. Assistant Chair-Dept of Obstetrics, Gynecology&Reproductive Biology
name: Asgerally T. Fazleabas, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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. doi: 10.1093/humupd/8.4.333.
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.
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. doi: 10.1073/pnas.96.5.2543.
citation: 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.
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.
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. doi: 10.1210/en.2006-0832. Epub 2006 Nov 16.
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.
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.
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.
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.
citation: 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.