Hormonal Optimization: Late vs. Immediate Start After Discontinuation of Oral Contraceptives in Assisted Reproductive technologY (HOLIDAY) (HOLIDAY)

February 26, 2026 updated by: Kate Devine, Shady Grove Fertility Reproductive Science Center

A Randomized Blinded Controlled Trial Assessing Hormonal Optimization: Late vs. Immediate Start After Discontinuation of Oral Contraceptives in Assisted Reproductive technologY (HOLIDAY)

HOLIDAY is a two-arm, parallel-group, multi-center, randomized trial in which subjects undergoing planned oocyte cryopreservation will be randomized to receive either a 2-month pause of Combined Hormonal Contraceptives (CHC) or immediate start (without a pause).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Reproductive aging in women is a continuous process that begins prior to birth and extends until menopause. The primary mechanism behind this process is the depletion of the ovarian pool of non-growing follicles (NGFs). Previous models, such as the biphasic-exponential model, have postulated that female fertility prominently declines with age, significantly after age 32, and with a more accelerated rate after age 35. Newer models of ovarian follicular depletion predict no sudden change in decay rate but rather a constantly, increasing rate.

With the advent of vitrification, oocyte cryopreservation has become a powerful tool to help preserve female fertility potential against anticipated gamete exhaustion. At the same time, as more women choose to delay childbearing for various reasons, planned oocyte preservation is increasing in popularity. Continued optimization of protocols has led to improved outcomes with good oocyte yields. For women undergoing oocyte cryopreservation who are not actively attempting to conceive, endometrial development does not need to be synchronized with the oocytes. Thus, ovarian stimulation can be initiated irrespective of the phase of the menstrual cycle without adversely impacting oocyte yield or quality, thereby facilitating scheduling and reducing delays.

Many patients are utilizing combined hormonal contraception (CHC) at the time of their initial oocyte cryopreservation consultation. In the United States, about 14% of women aged 15-49 were using oral contraceptive pills (OCPs) in 2017-2019. While a short course of CHC exposure is unlikely to be detrimental to oocyte yield, longer-term CHC use may lead to significant suppression of the hypothalamic-pituitary-ovarian axis, gonadotropins, and in turn, follicular development. After only 3 months of CHC use, studies have demonstrated that the pituitary response to gonadotropin-releasing hormone is blunted. If hypothalamic-pituitary suppression from CHC prevents progression of follicle development to the antral stage, prolonged use may also lower the number of follicles susceptible to exogenous gonadotropin stimulation for oocyte collection and therefore total oocyte yield. Patients may require additional cycles and incur additional expense to achieve the desired number of cryopreserved oocytes.

It has been well demonstrated that markers of ORT, specifically, antral follicle count (AFC) and Anti-Müllerian hormone (AMH) are good predictors of oocyte yield. Existing evidence suggests that CHC use can suppress and diminish these measures of ovarian reserve by 20-30% via suppression of follicle-stimulating hormone (FSH). One study found that that long-term CHC user could increase AMH by 53% and AFC by 41%, with values returning to normal within 2 months and a plateau effect thereafter. Similarly, another study found after stopping long-term CHC use for 2 months, there was an average increase in AFC of 4.

Overall, existing literature regarding the association between hormonal contraceptive use and AMH concentration has historically been inconsistent but more recent data with large sample sizes, including a systematic review, concluded that AMH levels in women using CHC more than 6 months appears to markedly decline with recovery after discontinuation. Reproductive-age women with lower AMH percentiles at baseline may experience a greater suppressive effect from prolonged CHC use, while it is speculated that those with higher AMH percentiles at baseline may experience a lesser suppressive effect.

There are abundant observational data suggesting long-term CHC use is associated with reversable suppression of ovarian reserve markers, with biologic plausibility that this in turn may mask the "true biological potential" of the ovaries and possibly result in suboptimal oocyte yield. However, to date there are no published adequately powered prospective randomized data evaluating whether a contraceptive pause would lead to improved outcomes. Such practices may already be taking place in ART centers. The simple act of waiting for the potential of more oocytes takes on an obvious, low-risk appeal. Therefore, the investigators propose this assessor-blind, randomized clinical trial comparing a 2-month contraceptive pause to immediate oocyte cryopreservation, with oocyte yield as the primary outcome.

Study Type

Interventional

Enrollment (Estimated)

394

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Connecticut
      • Orange, Connecticut, United States, 06477
    • Maryland
    • New York
      • New York, New York, United States, 10022
        • Not yet recruiting
        • Reproductive Medicine Associates of New York
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Ovary-bearing individuals 18 to 40 years of age.
  2. BMI < 40 kg/m2
  3. Non-smoker for at least 3 months prior to study enrollment.

Exclusion Criteria:

  1. BMI greater than or equal to 40 kg/m2
  2. Current Smoker
  3. Any contraindications to ovarian stimulation or outpatient egg retrieval under anesthesia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Holiday
Patients will undergo a 2 month drug holiday (pause) with combined hormonal contraceptives prior to planned oocyte cryopreservation
Other: OCP pause
Subjects in the study arm will be asked to discontinue combined hormonal contraceptives (CHC) for 2 months prior to planned oocyte cryopreservation
No Intervention: Immediate Start
Patients will immediately begin planned oocyte cryopreservation after discontinuation of prolonged combined hormonal contraceptive

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Oocyte maturation rate
Time Frame: During oocyte retrieval
Median number of percentage of vitrified MII oocytes yielded per cycle
During oocyte retrieval
Number of oocytes retrieved
Time Frame: During oocyte retrieval
The median number of cumulus-oocyte complexes (COC) retrieved during oocyte retrieval
During oocyte retrieval

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
AMH levels
Time Frame: AMH level differences from baseline to post-drug holiday (2 months)
Differences in AMH levels from baseline to cycle start
AMH level differences from baseline to post-drug holiday (2 months)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Shady Grove Fertility Reproductive Science Center

Collaborators

EMD Serono

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 25, 2026

Primary Completion (Estimated)

June 1, 2027

Study Completion (Estimated)

July 1, 2027

Study Registration Dates

First Submitted

November 4, 2025

First Submitted That Met QC Criteria

November 4, 2025

First Posted (Actual)

November 10, 2025

Study Record Updates

Last Update Posted (Actual)

March 2, 2026

Last Update Submitted That Met QC Criteria

February 26, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • Pro00090115

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

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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