Effect of hCG on Receptivity of the Human Endometrium
Condition: Infertility; Subfertility
MeSH terms: Infertility
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): human chorionic gonadotropin (hCG); Placebo Comparator (for hCG)
Intervention type(s): Drug; Drug
Intervention description(s): 500IU of hCG diluted to a final volume of 50ul in IVF media ("Global"-trademark); 50ul of IVF medium ("Global"-trademark) to mimic hCG infusion
Other intervention name(s): Novarel, human chorionic gonadotropin; IVF media; "Global" media-trademark
Intervention MeSH terms: Chorionic Gonadotropin
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: embryo; implantation; blastocyst; in vitro fertilization; human chorionic gonadotropin