What is priming and why is it done?

Priming is the term used to describe preparation or pre-treatment in the cycle(s) prior to starting in vitro fertilization (IVF). Both males and females going through fertility treatment can use a range of priming drugs or protocols, though many patients will not do any priming at all. Priming can also be used in the case of oocyte cryopreservation (egg freezing without IVF), but this article will focus exclusively on IVF.

Priming is often used to modify the hormonal system to synchronize follicle development. One common type of priming involves oral contraceptive pills, also known as birth control pills (BCPs). Typically, BCPs are started during the luteal phase of the menstrual cycle that occurs prior to the IVF cycle. The goal is to quiet the ovaries in advance of stimulation. This step may allow more follicles to increase in size at a similar rate (i.e. synchronized follicle development) and may even prevent cysts.ⁱ Estrogen priming is another type of priming that is intended to help synchronize follicle development;ⁱⁱ both types of priming are discussed in detail below.

Some IVF patients will have a poor ovarian response (POR) to controlled ovarian stimulation.ⁱⁱⁱ Priming is frequently used in these poor prognosis patients in an attempt to improve IVF outcomes in subsequent cycles. As such, some priming protocols are intended to improve the quantity or quality of eggs (also called oocytes) for egg retrieval or other fertility treatment. Examples of drugs used for POR include growth hormone (GH), dehydroepiandrosterone (DHEA), or testosterone. Supplements such as coenzyme Q10 (CoQ10) may be used as well.^iv,v

At what point in the cycle does priming start?

Priming protocols typically start in the month, or months, prior to the first day of the in vitro fertilization (IVF) cycle when the egg retrieval occurs. Sometimes the priming medications will continue into the first few days of the IVF cycle, and they may even overlap with stimulation medications.

The timing of each priming regimen varies:

• ‍Birth control pills (BCPs): Patients who are taking oral contraceptives as part of their priming regimen will do so in the menstrual cycle immediately before their IVF cycle. For example, they may take BCPs for a few days to over a month. The typical length of time is two to four weeks in the proceeding cycle.
• ‍Estrogen: The various types of estrogen priming will start in the menstrual cycle preceding the IVF cycle. The estrogen is typically stopped either before Day 1 of the IVF cycle or before the stimulation injections begin, although sometimes wearing an estrogen patch may overlap with the start of ovarian stimulation.
• ‍Growth hormone (GH): GH supplementation often begins weeks or even months prior to the start of the IVF cycle and may also be used during the stimulation cycle.  

What drugs or supplements are used for priming and pre-treatment in advance of ovarian stimulation?

The different types of priming approaches are summarized in Table 1.  Read on for more information on each individual priming regimen.

References: ^{vi,vii,viii,ix,x,xi,xii,xiii,xiv}

Birth control pills (BCP)

Birth control pills (BCPs) are a common priming methodology used in traditional in vitro fertilization (IVF) protocols. They are typically taken during the menstrual cycle prior to IVF, for varying lengths of time, such as 21 days.

Here are some reasons BCPs may be used as a priming protocol:

• ‍Scheduling assistance: They can make the patient’s next period start on a particular date, so they are often used by IVF patients and clinics to coordinate the start date of controlled ovarian stimulation (COS, known by patients as "stims" or stim injections).^xv This method of scheduling also helps in planning egg retrievals, as it allows clinics to potentially avoid retrievals on certain days that could be inconvenient for the patient or when the IVF clinic is closed.
• ‍Syncing of follicle growth: BCPs hormonally suppress or "quiet" the ovaries before IVF stimulation. This process may allow for synchronization of follicle growth by slowing the premature growth of follicles and allowing the follicles to grow more evenly in size. The goal of syncing follicle sizes is to encourage eggs to reach maturity at approximately the same time, which may allow for better mature oocyte yield.^xvi
• ^‍Prevention of cysts: BCP treatment can help prevent cyst formation.^xvii

Most evidence suggests that taking oral contraceptives prior to IVF does not impact IVF outcomes. For example, a 2019 study of more than 5,000 females undergoing IVF found no significant differences between clinical pregnancy and live birth rates in females receiving BCP pre-treatment compared to those individuals not taking BCPs.^xviii Furthermore, a meta-analysis of 29 randomized controlled trials concluded that there was insufficient evidence to support a difference in pregnancy and live birth rate when using BCP pre-treatment compared to no pre-treatment.^xix

In contrast, other studies show that pre-treatment in the previous IVF cycle with birth control has been associated with a lower live birth rate.^xx For example, one study showed a reduction in the live birth rate after fresh transfer (53 percent with no BCP and 43 percent with BCP pre-treatment).^xxi In addition, the ESHRE ovarian stimulation guidelines recommend that females do not do BCP pre-treatment when using an antagonist protocol.^xxii

It is important to keep in mind that there are instances where BCP pre-treatment may not be recommended. Older females and females with diminished ovarian reserve (DOR) may be advised against BCP pre-treatment as it could potentially lead to slightly longer ovarian stimulation protocol length and increased dosage of stimulation drugs compared to other types of priming.^xxiii More importantly, some experts believe that it may over-suppress the ovaries and endometrium without improving oocyte retrieval or pregnancy outcomes.^xxiv

Estrogen

Estrogen (estradiol) pre-treatment is another common priming protocol.^xxv It is often suggested for patients with poor ovarian response who are using a standard GnRH antagonist protocol. It is not used for patients who are priming with BCPs.

It is believed that estrogen priming works by suppressing the secretion and activity of natural GnRH and helps prevent early development of a lead follicle during the IVF stimulation period. By preventing an early increase in follicle stimulating hormone (FSH) levels, the aim is to synchronize the development of follicles so that they grow more evenly.^xxvi,xxvii In other words, it helps to yield more follicles that are of a similar size instead of follicles being a large range of sizes at retrieval time. As a result, it may allow for the retrieval of more mature oocytes.

Oral estrogen (e.g., Progynova® or Estrace®) priming is typically started in the luteal phase of the menstrual cycle that occurs prior to IVF stimulation and egg retrieval. (Note: The luteal phase is the part of the menstrual cycle after ovulation.) Estrogen is typically stopped on Day 2 or 3 of the next cycle (which is the IVF cycle), just prior to starting gonadotropin injections (e.g. Gonal-f®, follistim(R),  or Menopur®).^xxviii

The timing of prescribed estrogen is variable. One study compared the effect of stopping oral estrogen priming on Day 3 of the IVF cycle (before stimulation injections) versus continuing until the trigger shot in poor responders undergoing IVF.^xxix Both regimens reduced cycle cancellation rates and improved the number of eggs retrieved and the number of good quality embryos produced. The researchers also observed that continuing to take oral estrogen pills until trigger day slightly increased ongoing pregnancy rates from 20 percent to 27.1 percent.^xxx However, this result was not statistically significant.

Another delivery route for estrogen priming is the transdermal patch (e.g. Climara®, Estraderm®, Vivelle-dot®). The patch delivers estrogen (also called estradiol) across the skin into the bloodstream. It is intended to deliver the estrogen at a steadier rate. Patients start the estradiol patch in the luteal phase of the menstrual cycle prior to IVF, directly after a natural luteinizing hormone (LH) surge. The patch is changed every two to three days and typically stopped prior to ovarian stimulation during the IVF cycle.^xxxi The use of the patch sometimes overlaps with ovarian stimulation injections, but this is less common.

A modified version of these protocols involves estrogen priming followed by early administration of a GnRH antagonist (e.g. Cetrarelix/Cetrotide®). GnRH antagonists are used to prevent early ovulation during ovarian stimulation. They are typically started as the follicles get larger, around Day 7 to 9 of the IVF cycle. However, in this early follicular antagonist priming protocol, the antagonist injections are started as early as Day 1 or 2 of the IVF cycle.^xxxii,xxxiii

There are several studies supporting improved outcomes with estrogen priming, although overall the evidence on its impact is mixed.

A 2019 study published in Gynecological Endocrinology showed that luteal-phase estrogen pre-treatment had different benefits for poor responders and normal responders. They observed that among 148 patients with poor responses to ovarian stimulation, estrogen pre-treatment significantly decreased the cycle cancellation rate by 11 percent. It also increased the live birth rate.^xxxiv

Estrogen priming appears to provide the most benefit in cases of advanced age and/or diminished ovarian reserve (DOR), in particular for patients who have had previous failed IVF cycles.^xxxv A meta-analysis of eight studies in poor responders compared 468 females undergoing IVF with estrogen priming to 621 females without estrogen priming.^xxxvi The researchers observed that patients with estrogen priming had a lower risk of cycle cancellation and improved clinical pregnancy rate.^xxxvii

One randomized controlled trial examined oral estrogen pre-treatment before a GnRH antagonist protocol and reported no significant differences between the average number of mature eggs, endometrial thickness, and embryo quality or pregnancy rate, compared to cycles with no priming or BCP pre-treatment.^xxxviii

Researchers have also investigated the effect of combining estrogen with earlier Day 2 GnRH antagonist pre-treatment for poor responders.^xxxix In a retrospective study, they observed an increased number of retrieved and mature eggs that produced good quality embryos, as well as a 16 percent increase in the live birth rate; this increase was deemed statistically significant.^xl

Human growth hormone (GH)

Growth hormone is sometimes used as an add-on or priming drug for certain patients. Often it is added for patients with poor ovarian reserve, advanced maternal age, polycystic ovary syndrome (PCOS), or poor oocyte and/or embryo quality. Unlike with other priming protocols, there is no strictly prescribed timing for growth hormone supplementation. Taking GH can begin a few months prior to the start of IVF, in the weeks immediately before an IVF cycle, or during the cycle itself.

Various studies have reported a positive impact of GH supplementation in IVF protocols for patients with poor responses and/or older age.^{xli,xlii,xliii,xliv,xlv,xlvi,xlvii} However, others have reported contradicting results with no improvement in implantation and clinical pregnancy rates.^xlviii,xlix

One study published in 2020 investigated the effect of four or more weeks of low-dose GH pre-treatment in 92 females with diminished ovarian reserve (DOR).^l Investigators observed GH priming increased the number of retrieved eggs and transferable Day 3 (cleavage stage) embryos, as well as cumulative pregnancy rates. However, the clinical and ongoing pregnancy rates per fresh embryo transfer were similar between the growth hormone and control groups, and live birth rates were not reported. The author suggested that four weeks of GH treatment may potentially improve ovarian response in females with DOR, but that more research is needed.^li

A meta-analysis of 12 randomized controlled trials compared IVF outcomes in 586 females using GH supplementation to 553 females not taking growth hormone.^lii Researchers reported that while GH documentation did improve clinical pregnancy rates in poor responders, overall GH supplementation did not increase live birth rates in any patient groups.^liii

Ultimately, the results from studies on IVF protocols using growth hormone are inconsistent, and outcomes may depend on the dose and length of priming with GH, as well as the type of patient using GH. It can be an expensive drug, and the lack of consensus makes it difficult for IVF patients to determine whether to add on this priming option. As of 2023, the European Society of Human Reproduction and Embryology (ESHRE) does not recommend the routine use of GH before or during ovarian stimulation.^liv

Lupron®

Lupron® is a GnRH agonist that is used in an agonist protocol, such as the long agonist protocol. It can start in the menstrual cycle preceding egg retrieval, and its purpose is to suppress ovulation by depleting the pituitary gland of its follicle stimulating hormone (FSH) and luteinizing hormone (LH) stores.^lv Using the GnRH agonist in the previous cycle can help prevent a surge of LH during ovarian stimulation in the IVF cycle.^lvi

A GnRH agonist like Lupron® is technically not used for priming, and rather is part of the agonist protocol (used for pituitary suppression). Some patients may incorrectly perceive it as a separate add-on pre-treatment because it is started in the cycle preceding Day 1 of the IVF cycle.

Progesterone (progestin/progestogen)

A more recent protocol uses progestins (synthetic progesterone) to help prevent a premature luteinizing hormone (LH) surge.^{lvii,lviii,lix} This surge is more likely to occur in older females and patients with diminished ovarian reserve (DOR), and often leads to the cancellation of the IVF cycle.^lx,lxi

Progestin-primed ovarian stimulation (PPOS) uses oral drugs instead of injections, making it more patient-friendly (lower cost and fewer injections compared to Lupron or GnRH antagonist protocols). PPOS is usually started on Day 3 of the IVF cycle, at the same time as gonadotropin injections.^lxii The intent of PPOS is not pre-treatment or priming per se, but it is included here as it often gets grouped within these categories by patients.

A 2021 meta-analysis of several randomized controlled trials reported that clinical pregnancy and live birth rate were not significantly different between the PPOS and control groups.^lxiii However, the PPOS protocol did reduce the rate of premature LH surge in ovarian hyperstimulation syndrome. It also increased the number of eggs retrieved in patients with diminished ovarian reserve.^lxiv

In progestin-primed ovarian stimulation protocols, embryos must be frozen and thus a fresh transfer is not possible.

Androgen priming (testosterone and DHEA)

Androgen priming (using testosterone or DHEA) is a choice for some females with diminished ovarian reserve, poor ovarian reserve, or conditions related to low androgen production. Androgen supplementation is believed to potentially increase estrogen production and help follicles better respond to follicle stimulating hormone (FSH), because follicular cells have androgen receptors.^lxv

Testosterone is commonly administered as a testosterone gel (10 to 25 mg per day), a transdermal patch (2.5 mg per day), or oral capsule (40 mg per day).^lxvi However, reported dosages and duration (ranging from five to 51 days before starting ovarian stimulation) varied between randomized controlled trials.^lxvii

In addition, the European Society of Human Reproduction and Embryology (ESHRE) does not currently recommend routine use of DHEA or testosterone before or during ovarian stimulation, as the current research does not support its routine implementation.^lxviii

Coenzyme Q10 (CoQ10)

Low levels of CoQ10 are often associated with older IVF patients, diminished ovarian reserve, and increased rate of embryo aneuploidy (chromosomal abnormalities).^lxix

While not a true priming protocol, CoQ10 supplementation is thought to reduce oxidative stress and improve mitochondrial function, which is important in egg and embryo development. The idea is that CoQ10 supplementation will improve the response of the ovaries to stimulation and decrease the chance of aneuploid embryos in patients with diminished ovarian reserve.^lxx

CoQ10 is typically taken by pill with a dosage of 200 mg, three times daily, for 60 days before the IVF egg retrieval cycle. One small randomized controlled trial of 169 patients found that CoQ10 pre-treatment increased the number of eggs retrieved from patients with poor ovarian response.^lxxi A recent meta-analysis of 16 studies found that CoQ10 supplementation improved IVF, clinical pregnancy, and live birth rate in individuals with poor ovarian response.^lxxii However, overall research studies on CoQ10 are lacking and it is not currently recommended for routine use to improve live birth rates.^lxxiii,lxxiv

Male priming protocols

High levels of reactive oxygen species (ROS) — toxic byproducts created after cells use up oxygen — can lead to sperm damage, while antioxidants can reduce ROS production and inhibit oxidation (chemical reaction).

Antioxidants are sometimes used to treat idiopathic (unknown cause) male factor subfertility, or as a pre-treatment before starting assisted reproductive technology (ART) cycles. This step can protect sperm from oxidative stress damage. However, some levels of ROS are important for proper sperm maturation.^lxxv

Common antioxidant versions include single or combined oral supplements, such as vitamins E and C, CoQ10, and the micronutrients, folate, selenium, and zinc.^lxxvi A 2020 randomized controlled trial published in Human Reproduction Open investigated the effect of oral antioxidant supplementation (zinc and vitamins C and E) in males for three months before starting an ART cycle. The study reported some differences in clinical pregnancy rates between the antioxidant pre-treatment group (36 percent) and the group with no pre-treatment (26 percent). However, the differences were not statistically significant. There was also no significant improvement in sperm concentration, motility, and morphology after antioxidant pre-treatment.^lxxvii

To date, no supplements for male factor infertility have been consistently proven to improve live birth rates. Many providers may simply recommend that males take a daily multivitamin and improve lifestyle habits for at least three months prior to and during fertility treatment.

Conclusion

Successful IVF outcomes hinge on retrieving high-quality eggs that will lead to a live birth. To properly stimulate the ovaries, a priming protocol may be recommended to some females undergoing IVF. The time and duration of priming protocols varies depending on a number of factors. For anyone planning to pursue IVF, it is useful to understand the different types of priming protocols and why a particular one might be advised over another. Ultimately, a fertility doctor will recommend the protocol that seems most appropriate for the patient, which is often based on the patient's response in a prior IVF cycle. Importantly, what works well for one patient may not work as well for another.