Endometrial Luteal Phase Characteristics and Luteal Phase Support in Controlled Ovarian Stimulation Protocols With GnRH Antagonists:Focusing on MicroRNA

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Yulian Zhao, Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT01510054
First received: December 22, 2011
Last updated: January 10, 2012
Last verified: January 2012
  Purpose

MiRNAs are single-stranded small non-coding RNAs that act on specific mRNAs to regulate the gene expression. Studies have suggested that miRNAs influence cellular activities in the uterus, including cell differentiation and embryo implantation.

In assisted reproductive cycles, controlled ovarian stimulation (COS) results in supraphysiological steroid levels and is associated with very low luteinizing hormone concentration during the luteal phase, the peri-implantation and implantation period. Luteal phase support, administration of medication aimed at supporting the implantation process, has been a routine practice in in vitro fertilization (IVF) clinics. Luteal phase support with steroid hormone has been found to improve pregnancy rates when human menopausal gonadotropins were used in conjunction with GnRH agonists for ovarian stimulation and IVF. Reports on effect of steroid supplementation in GnRH antagonist protocols are limited.

The proposed project is an extension of our previous study on Endometrial Luteal Phase Characteristics and Luteal Phase Support in Controlled Ovarian Hyperstimulation Protocols with Gonadotropin Releasing Hormone Antagonists. The significance of this study is based on the importance of luteal phase endometrial after COS for the process of implantation. The availability of oocycte donors in assisted reproduction technology programs offers a unique opportunity to study the impact of different stimulation protocols on the quality of the luteal phase. In addition, the oocyte donor model may allow us to evaluate the impact of different luteal support protocols directly on the endometrial preparation by histological as well as biochemical markers.

Study design: Study subjects underwent ovarian stimulation according to a gonadotropin/GnRH antagonist protocol. All donors had a baseline measurement of serum follicle stimulating hormone (FSH) and estradiol levels on the second day of their menstrual cycles. Provided serum FSH levels were less than 10mIU/ml and E2 levels were less than 60pg/ml, ovarian stimulation was initiated with recombinant FSH. The daily dose was adjusted according to follicular development by serial transvaginal ultrasound and serum E2 response. A daily evening dose of ganirelix acetate was initiated on the 6th day of stimulation and continued through the day of human chorionic gonadotropin administration. When at least three follicles reached a mean diameter of 18mm, ovulation was triggered with a single dose of Human chorionic gonadotropin (hCG). Sonographically guided transvaginal oocyte retrieval was performed 34-36 hours after the hCG administration.

Thirty endometrial biopsies from oocyte donors on their COS cycles will be used for the study. Study subjects have been randomized into 4 groups. Grp 1: day of retrieval, did not receive any luteal-phase support, which serves as base line; grp2: 3, 5 and 10 days after retrieval with no luteal phase support, which serves as control; grp3: 3, 5 and 10 days after retrieval, luteal phase support with progesterone in the form of vaginal suppositories starting from the day after retrieval; grp4: daily oral dose of 2 mg 17β-estradiol in addition to the micronized progesterone. Immediately after the endometrial biopsy all specimens were stored in liquid nitrogen tanks at -196°C.

Total RNA will be isolated and microarray will be performed using an Illumina miRNA expression panel. Array results will be compiled and analyzed focusing on the following aspects: the target genes of prominent miRNAs, miRNA profile in relation to target gene pathways; miRNA expression profile in relation to endometrial dating and status; effect of luteal phase support on miRNA expression after ovarian stimulation. Minimum of 3 miRNA arrays will be run for each sample for the purpose of statistical analysis. A total of 30 arrays will be needed for all samples from all groups.

In this study, the investigators pose three questions: 1) How many and what types of miRNAs are in the endometrium during ovarian stimulation? This is to identify miRNAs and associated target genes that are relevant for endometrium receptivity; 2) Do levels of miRNA expression change during the luteal phase, or during the window of implantation? This is to examine the dynamics of miRNAs that are associated with remodeling process of endometrium; and 3) Do luteal phase support alter miRNA expression in the luteal phase? This is to investigate the steroid effect on miRNA regulation. The investigators hypothesize that many critical genes related to implantation are regulated by miRNAs. This research effort will potentially advance our knowledge of endometrial characteristics after COS and the impact of sex steroid supplementation. Overall the study should help better understand the genetic control of implantation. Completion of this study may also provide measurable scientific evidence and useful information for the management of IVF cycles.


Condition Intervention
Controlled Ovarian Stimulation
Drug: progesterone and estrogen
Drug: GnRH antagonist
Drug: gonadotropin, hCG

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Single Blind (Subject)
Primary Purpose: Health Services Research
Official Title: Endometrial Luteal Phase Characteristics and Luteal Phase Support in Controlled Ovarian Stimulation Protocols With Gonadotropin Releasing Hormone (GnRH) Antagonists: Focusing on MicroRNA Identification and Expression

Resource links provided by NLM:


Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:
  • microRNA expression in human endometrium after IVF [ Time Frame: Up to 4 years are estimated for the study to be completed including all measures. ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: July 2002
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: steroid support
Endometrial biopsies from subjects of with or without luteal phase steroid support will be compared for miRNA expression
Drug: progesterone and estrogen
progesterone or/and estrogen is routinely used in standard IVF procedures. The purpose of this study is to compare miRNA gene expression in the endometrium with or without steroid support.
Drug: GnRH antagonist
During ovarian stimulation, a daily evening dose of 0.25mg ganirelix acetate (GnRH antagonist)is given subcutaneously, for approximately 6 days. This is to prevent LH surge so as to control the reproductive cycle.
Other Name: ganirelix acetate
Drug: gonadotropin, hCG
Gonadotropin is used to simulate ovarian follicle growth and is routinely used for in vitro fertilization procedures clinically. hCG (10,000IU once) is administered to trigger oocyte maturation and ovulation.
Other Name: FSH for gonadotropin

  Eligibility

Ages Eligible for Study:   21 Years to 31 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 21 to 31 years of age female who underwent a standard screening protocol for oocyte donation, in accordance with the recommendations of the American Society for Reproductive Medicine.

Exclusion Criteria:

  • Women with a body mass index exceeding 28 kg/m2,
  • history of:

    • pelvic inflammatory disease,
    • sexually transmitted diseases,
    • reproductive tract pathology, or
    • other systemic diseases or conditions
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01510054

Locations
United States, Maryland
Johns Hopkins at Green Spring Station
Lutherville, Maryland, United States, 21093
Sponsors and Collaborators
Johns Hopkins University
Investigators
Principal Investigator: Yulian Zhao, Ph.D Johns Hopkins University
  More Information

No publications provided

Responsible Party: Yulian Zhao, Associate Professor, Johns Hopkins University
ClinicalTrials.gov Identifier: NCT01510054     History of Changes
Other Study ID Numbers: IISP 38749
Study First Received: December 22, 2011
Last Updated: January 10, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Johns Hopkins University:
miRNA in endometrium

Additional relevant MeSH terms:
Estrogens
Progesterone
Ganirelix
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Progestins
Hormone Antagonists

ClinicalTrials.gov processed this record on August 20, 2014