Delayed Start to Ovarian Stimulation (DOS/DOR)

Delayed Start to Ovarian Stimulation Improves Oocyte Maturation and Quality: A Randomized Trial

In couples with infertility secondary to Diminished Ovarian Reserve, the investigators hypothesize that a delayed start (7 day) to ovarian stimulation with an GnRH antagonist (Ganirelix) will improve oocyte maturation and quality, and improve pregnancy outcomes.

Study Overview

• Status: Terminated
• Conditions: Infertility; In Vitro Fertilization; Diminished Ovarian Reserve
• Intervention / Treatment: Drug: Ganirelix acetate

Detailed Description

Over the past two decades, the success rate of assisted reproductive technology (ART) has dramatically increased. This increase is attributed to improvements in embryo culture, laboratory conditions, and optimization of ovarian stimulation protocols. Over the past years, there has been more interest in altering the ovarian stimulation protocol to improve outcomes. For example, recently our group found that a modification of ovulation trigger toward a more physiologic process improves oocyte quality and pregnancy outcomes. Others have suggested minimal stimulation improves in vitro fertilization (IVF) outcomes. The investigators propose to further investigate modifying the ovarian stimulation for women who have "decreased" ovarian reserve. The investigators propose that a delayed start to ovarian stimulation will improve oocyte maturation and quality and pregnancy outcomes. No published studies to date have evaluated if a delayed start to ovarian stimulation improves pregnancy outcomes. However, the investigators hypothesize that the use an antagonist for a delayed start of stimulation will work by one of two mechanisms:

I. The partial suppression of FSH will allow for further recruitment of early antral follicles.

II. The partial suppression of FSH will allow for further FSH responsiveness in existing follicles to synchronize the primary cohort, thereby increasing the total number of follicles.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115
      • UCSF Center for Reproductive Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Antral Follicle Count (AFC) less than or equal to 4 as measured by transvaginal ultrasound (TVUS), or
• Cancellation of a prior IVF cycle due to poor ovarian response.
• Patients will receive an antagonist stimulation protocol for IVF, or IVF with Intracytoplasmic Sperm Injection (ICSI).

Exclusion Criteria:

• Severe male factor infertility requiring surgical intervention to obtain sperm
• Major uterine abnormality,
• Preimplantation genetic diagnostic (PGD) testing,
• Planned cycles without embryo transfer (for example, freeze-all, donor, or surrogate cycles).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Delayed Start; Study subjects will receive 7 days of pre-treatment with a GnRH antagonist (Delayed Start) before standard ovarian stimulation with FSH/LH.	Drug: Ganirelix acetate; Subjects will receive 7 days of pre-treatment with the GnRH antagonist; Other Names: Ganirelix
Active Comparator: Conventional Start; Ovarian stimulation with standard antagonist protocols (no delay).	Drug: Ganirelix acetate; Subjects will receive 7 days of pre-treatment with the GnRH antagonist; Other Names: Ganirelix

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fertilization Proportions	Developmental competence (fertilization of oocytes) through standard in vitro fertilization (estimated time frame to be between 8-24 hours following IVF). This percentage will be calculated as the number of fertilized eggs ( 2PN stage) per total number of eggs collected from the egg retrieval.	8 to 24 hours after in vitro fertilization, oocytes will be checked for fertilization
Number of Oocytes Retrieved	The egg retrieval procedure will be performed 36 hours after the ovulation trigger. The procedure is estimated to take up to 1 hour at study visit as part of routine care. The number of retrieved eggs will be counted	up to 1 hour after oocytes retrieved

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Embryo Quality	Embryo quality will be assessed by the embryologist on days 2 or 3 (Cleavage stage) following IVF using standard embryo grading criteria. Embryos grading is based on three criteria: the number of blastomere cells present in the embryo, the degree of observed cell fragmentation and the degree of observed symmetry of the cells.	One hour on day 2 or 3 (following IVF procedure)
Pregnancy Rates	Beta HCG levels will be assessed at 2 weeks and 3 weeks after embryo transfer. A positive pregnancy is defined as two positive beta HCG levels (a value > 5 mIU/ml ) observed over the time frame.	2 to 3 weeks following embryo transfer
Stages of Oocyte Nuclear Maturation	Quality of oocytes will be assessed for developmental stages (Germinal Vesicles, Meiosis I, or Meiosis II)	average of 1 to 2 hours on the Day of Retrieval
Number of Mature Follicles	Maturation of follicles will be assessed by measuring the size of follicles (mature > 13mm) prior to (or at the time of) oocytes retrieval.	up to 1 hour (during the Transvaginal Ultrasound before Retrieval of Oocytes)
Oocyte Recovery Rate	The number of oocytes recovered at the time of oocyte retrieval following ovarian stimulation.	up to 1 hours after oocyte retrieval

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Mitchell Rosen, MD, UCSF Center for Reproductive Health and Fertility Preservation

Publications and helpful links

General Publications

• Blockeel C, Riva A, De Vos M, Haentjens P, Devroey P. Administration of a gonadotropin-releasing hormone antagonist during the 3 days before the initiation of the in vitro fertilization/intracytoplasmic sperm injection treatment cycle: impact on ovarian stimulation. A pilot study. Fertil Steril. 2011 Apr;95(5):1714-9.e1-2. doi: 10.1016/j.fertnstert.2011.01.028.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: May 2, 2012
• First Submitted That Met QC Criteria: June 4, 2012
• First Posted (Estimate): June 7, 2012

Study Record Updates

• Last Update Posted (Actual): June 15, 2021
• Last Update Submitted That Met QC Criteria: May 20, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: IVF; Infertility; ART; GnRHa; DOR; GnRH Antagonist Protocol; Ganirelix
• Additional Relevant MeSH Terms: Infertility; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Ganirelix
• Other Study ID Numbers: UCSF 11-07259

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes