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

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.

• AMH levels [Time frame: AMH level differences from baseline to post-drug holiday (2 months)]