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 fertility treatment; this includes using ovarian stimulation drugs for IVF. Both men and women going through fertility treatment can use a range of priming drugs or protocols, though some patients will not do any priming at all. This will be determined by a patient’s medical provider.

Pre-treatments are often used to modify the hormonal system to synchronize follicle development in patients who respond poorly as well as those who respond normally. The most common type of priming involves oral contraceptive pills, also known as birth control pills (BCPs). Typically, BCPs are started in the previous cycle (the luteal phase) to quiet the ovaries in advance of stimulation. Doing this may allow for more follicles to increase in size at a similar rate (i.e., synchronized follicle development) and may prevent cysts. It also helps with logistical timing of the ovarian stimulation cycle.ⁱ

Other priming protocols are intended to get a higher quantity or improved quality of oocytes during egg retrieval or other fertility treatment. These include drugs such as growth hormone, dehydroepiandrosterone (DHEA), or testosterone. It also includes supplements such as coenzyme Q10 (CoQ10).^ii,iii Among IVF patients, 5.6 to 35.1 percent will have a poor ovarian response (POR) to controlled ovarian hyperstimulation. Priming is frequently used in these patients in an attempt to improve IVF outcomes in subsequent cycles.^iv

‍

At what point in the cycle does priming start?

Patients who are taking BCP as part of their priming regiment will do so for about ten days starting from the luteal phase of the previous cycle (around day 20 or day 21). Gonadotropin injections (Gonal-F®) begin approximately six days after the patient stops taking BCPs.^v Typically, at this point cycle day (CD) 1 (i.e., first day of full menstrual flow) has occurred when injections start.

One of the common priming protocols is called the agonist protocol. At the beginning of a new menstrual cycle—and before starting controlled ovarian stimulation (COS)—priming begins with a flare protocol, which includes a microdose of the gonadotropin releasing hormone (GnRH) agonist Lupron®. For patients who are taking BCPs, the flare protocol microdose starts after the BCP regimen is complete. Then, gonadotropin injections begin after the start of GnRH agonist priming. Injections continue daily until human chorionic gonadotropin (hCG) trigger day.^vi

While patients have a few options for estrogen priming, all protocols start in the cycle preceding an IVF cycle. One option is oral estrogen (e.g., Progynova®) priming, which can be started on day 21 of the luteal phase of a previous natural cycle during which the patient does not take BCPs. It can be stopped at day 3 of the following IVF cycle before starting Gonal-f® gonadotropin injections. It could also be continued during COS until the trigger day, including hCG trigger day.^vii

Another option is an estrogen patch in combination with a GnRH antagonist. With this, patients start the estradiol patch (e.g., Climara®) in the previous cycle after a natural luteinizing hormone (LH) surge. The patch is changed every other day, and on the second day after beginning the estradiol patch, patients begin 0.25 mg injections of a GnRH antagonist (e.g., Orgalutran®) for three days. They then begin their COS protocol on day 2 of the next menstrual cycle.^viii  

There are variations of the estrogen-primed antagonist protocol. A modified version involves estrogen pre-treatment (e.g., Progynova®) in the late luteal phase of the previous cycle for 7 to 10 days. A GnRH antagonist injection (e.g., Cetrotide®) follows immediately on roughly day 2 of the following cycle. The injections continue for five days before starting COS.^ix This priming protocol is also known as the “early follicular GnRH antagonist priming protocol (E/G-ant).” After the E/G-ant pre-treatment, gonadotropin injections of Menopur® begin on day 7 (in the mid-follicular phase) and a GnRH antagonist will be injected again when the largest follicles measure more than 12 mm. Then, a trigger such as hCG will be administered when the leading follicle measures more than 18 mm.^x

Growth hormone is used for priming in some patients, though unlike with other priming protocols, there is no strict prescribed timing. This can begin a few months prior to the start of IVF, in the weeks immediately before an IVF cycle, or within the cycle itself.

‍

What drugs are used for priming in advance of ovarian stimulation?

‍

References: xi,xii,xiii,xiv,xv,xvi,xvii,xviii,xix,xx

‍

Birth Control Pills (BCP)

Birth control pills (BCPs) are the most common type of priming methodology used in traditional IVF protocols. They are often used by IVF patients and clinics to schedule and/or coordinate the start of the next COS cycle. BCP pre-treatment during the previous menstrual cycle suppresses gonadotropin release and helps schedule the patient’s period. This method of scheduling also helps in planning oocyte retrieval, as it potentially avoids retrieval on certain days that could be inconvenient for the patient or when the IVF clinic is closed.^xxi

BCPs hormonally suppress or “quiet” the ovaries before IVF stimulation. This process may allow for synchronization by slowing the premature growth of follicles and allowing the follicles to grow more evenly in size. When follicle sizes are synchronized, they will reach maturity at approximately the same time, which allows for better mature oocyte yield. When follicles do not grow at the same rate this is referred to as “splaying.” BCP treatment also prevents cyst formation and shortens the length of GnRH agonist/antagonist treatment.^xxii

A 2018 randomized controlled trial (RCT) study published in the International Journal of Reproductive Biomedicine compared BCP pre-treatment in 53 patients to no pre-treatment in 70 patients prior to starting IVF protocols. The study showed no significant differences between the groups with regard to the average number of mature oocytes, endometrial thickness, and embryo quality. The pregnancy rate was slightly higher in the BCP group (39.6 percent) than the no pre-treatment group (34.3 percent). However, this was not statistically significant.^xxiii

In addition, another 2019 study published in Reproductive Biomedicine Online compared the effect of BCP pre-treatment to no-pretreatment in more than 5 000 women who were undergoing traditional IVF protocols. The results found no significant differences between the two groups in clinical pregnancy and live birth rates.^xxiv

There are instances where BCP pre-treatment may not be recommended. Older women and women with diminished ovarian reserve (DOR) are often advised against BCP pre-treatment as it can lead to longer COH protocol length and increased dosage of stimulation drugs. Ultimately, it can over-suppress the ovaries and endometrium without improving oocyte retrieval or pregnancy rates.^xxv

‍

Estrogen

Estrogen (estradiol) pre-treatment is another common priming protocol, and one that is often suggested for patients who have poor ovarian response who are using a standard GnRH antagonist protocol. These patients take oral estrogen medication, such as Progynova®, or use a transdermal patch during the luteal phase in the cycle before starting IVF.

Among alternative IVF protocols, an estrogen priming protocol suppresses the secretion and activity of natural GnRH in the following cycle. In preventing an early increase in follicle stimulating hormone (FSH) levels, this method synchronizes the development of follicles so that they grow more evenly. As a result, this may promote the retrieval of more mature oocytes.^xxvi

Estrogen priming has been suggested to increase pregnancy rates in patients with poor ovarian reserve who have previous failed cycles. This is sometimes known as an estrogen primed antagonist protocol.^xxvii

A 2016 study published in Clinical and Experimental Reproductive Medicine compared transdermal estradiol and BCP pre-treatment in 2 092 patients. Researchers reported no significant differences for the number of total and mature oocytes retrieved or in pregnancy and live birth rates. However, they observed transdermal estradiol patches allowed for shorter COH protocol length and fewer gonadotropin injections than are required for oocyte retrieval in normal responders having fresh IVF transfer cycles.^xxviii

Another 2011 study published in Assisted Reproduction Technologies compared whether taking oral estrogen pills starting on day 21 of the previous cycle and stopping on cycle day 3 or continuing until the day of hCG trigger injection-improved reproductive outcomes for patients with poor response. Researchers observed estrogen pre-treatment lowered the cancellation rate by 22.6 percent, increased the number of oocytes retrieved (4.5 versus 3.2 oocytes), and increased production of good quality embryos by 26.2 percent. They also determined that continuing to take oral estrogen pills until trigger day slightly increased ongoing pregnancy rates to 27.1 percent from 20 percent. However, this result was not statistically significant.^xxix

In the previously mentioned 2018 study published in International Journal of Reproductive Medicine, this randomized control trial looked at oral estrogen pre-treatment before a GnRH antagonist protocol and reported no significant differences between the average number of mature oocytes, endometrial thickness, and embryo quality.^xxx Investigators in a 2019 study published in Gynecological Endocrinology showed that luteal estrogen pre-treatment had different benefits for poor and normal responders. They observed that among 148 patients with poor responses, estrogen pre-treatment significantly decreased the cycle cancellation rate by 11 percent. It also increased the live birth rate by 33 percent. Among the normal responder group, however, they observed pre-treatment significantly increased oocyte maturation by 9 percent.^xxxi

In another 2018 study published in Obstetrics and Gynecology Science, researchers investigated the effect of combining estrogen with earlier day 2 GnRH antagonist pre-treatment for poor responders. They observed an increased number of retrieved and mature oocytes that produced good quality embryos. Additionally, with the combined pre-treatment, they saw a 13.7 percent increase in the clinical pregnancy rate and a 16 percent increase in the live birth rate; this increase was deemed statistically significant.^xxxii

‍

Human Growth Hormone  

Growth hormone (GH) is sometimes used as an add-on or priming drug for certain patients. Typically, these patients have polycystic ovarian syndrome (PCOS), poor ovarian reserve, advanced maternal age, or poor oocyte and/or embryo quality.  

GH supplementation seems to be most promising when it is used in IVF protocols for patients with poor response and/or older age. Still, while some studies have shown positive results,^{xxxiii,xxxiv,xxxv,xxxvi,xxxvii,xxxviii,xxxix} others have reported no improvements in implantation and clinical pregnancy rates.^xl,xli Even among the most encouraging studies, many did not find an impact on live birth rates.

A 2020 study published in Gynecological Endocrinology investigated the effect of four or more weeks of low-dose GH pre-treatment in 92 women with DOR. Investigators observed GH priming significantly increased the numbers of retrieved oocytes, transferable day 3 (cleavage-stage) embryos, as well as cumulative pregnancy rates. They suggested that four weeks of GH pre-treatment could increase ovarian response in women with DOR.^xlii

An additional 2020 meta-analysis published in Fertility and Sterility analyzed 12 randomized controlled trials that compared GH supplementation in 586 women, with conventional COH without growth hormone in 553 women. Researchers reported that, overall, GH supplementation did not increase live birth rates, though it did increase the number of mature oocytes retrieved. The average increase was two oocytes. It also increased the number of embryos available to transfer, as well as the clinical pregnancy rates in poor responders.^xliii

Ultimately, the results from studies on IVF protocols using GH 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 navigate whether to add in this priming option.

‍

Lupron®

Lupron® is a GnRH agonist that is used in an agonist protocol, such as the long agonist. This starts in the menstrual cycle preceding egg retrieval. The purpose of using the GnRH agonist is to suppress ovulation by depleting the pituitary gland of its follicle-stimulating hormone (FSH) and LH stores.^xliv Using the GnRH agonist in the previous cycle prevents a surge of LH during ovarian stimulation.^xlv A GnRH agonist like Lupron® is technically not used for priming; some patients incorrectly perceive that it is because it is started in the cycle preceding cycle day 1of the egg retrieval. Lupron can also be used as a trigger shot in lieu of hCG, however in this case, it is also not a priming medication and is administered as a single dose 36 hours prior to egg retrieval.^xlvi  

‍

Progestin/Progestogen

A new priming protocol uses progestins to help prevent a premature LH surge that occurs in some GnRH antagonist cycles. This is more likely to occur in older females and patients with DOR, and often leads to cancelled COH cycles. Progestins should not be used for fresh transfer cycles because they can have a negative impact on endometrial receptivity.^xlvii

Progestin-primed ovarian stimulation (PPOS) is a new COH protocol that is often preferred for its ease of use, in that it uses oral drugs instead of injections, which lowers the cost of IVF. A 2021 meta-analysis of several randomized controlled trials focused on PPOS published in Frontiers in Endocrinology reported that clinical pregnancy and live birth rates were not significantly different between the PPOS and control group (patients with conventional COH). However, the PPOS protocol reduced the rate of premature LH surge and ovarian hyperstimulation syndrome. It also increased the number of oocytes retrieved in patients with diminished ovarian reserve.^xlviii PPOS is usually started on day 3—the early follicular phase—at the same time as gonadotropin injections.^xlix

‍

Other Female Priming Drugs

Androgen—testosterone or DHEA—priming has been used for some women with diminished ovarian reserve, poor ovarian reserve, or conditions causing low androgen production. Androgen supplementation can increase estrogen production or can prime follicles that have androgen receptors to better respond to FSH.^l Testosterone is commonly administered as a testosterone gel (10-25 mg/day), a transdermal patch (2.5 mg/day), or oral capsules (40 mg/day). However, reported dosages and durations (5-51 days before starting COH) varied between randomized controlled trials.^li,lii

Low levels of CoQ10 are often associated with older IVF patients, diminished ovarian reserve, and increased rate of embryo aneuploidy. While not a true priming protocol, CoQ10 supplementation can improve mitochondrial function, which may be important for maintaining ovarian reserve. Supplementation can also improve the response of the ovaries to stimulation and decrease the risk of aneuploidy in patients with diminished ovarian reserve.^liii CoQ10 pre-treatment is administered orally with a dosage of 200 mg, three times daily, for 60 days before COH. According to a 2018 randomized controlled trial published in Reproductive Biology and Endocrinology, CoQ10 pre-treatment increased the number of oocytes retrieved from patients with poor ovarian response.^liv

‍

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). Common antioxidant supplementation may include single or combined oral supplements, such as vitamins E and C, CoQ10 (ubiquinol), and the micronutrients folate, selenium, and zinc.^lv

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 can protect sperm from oxidative stress damage. However, some levels of ROS are important for proper sperm capacitation (maturation).^lvi

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 antioxidant pre-treatment and no pre-treatment, 36 percent versus 26 percent, respectively. However, these were not statistically significant. There was also no significant improvement in sperm concentration, motility, and morphology after antioxidant pre-treatment.^lvii

Many providers may simply recommend that sperm producing individuals take a daily multivitamin for at least three months prior to and during fertility treatment.  

‍

Conclusion

Success in IVF hinges on retrieving high-quality eggs that will lead to a live birth. In order to properly stimulate the ovaries, a priming protocol may be recommended to a woman undergoing IVF, and those protocols vary depending on a number of factors. For anyone planning to pursue IVF, it is important to understand the different protocols and why a particular one might be recommended over another. Depending on which study is read, different protocols may have higher, lower, or a similar success rate. Ultimately, a woman’s provider will select the protocol that seems most appropriate and will change protocols as needed based on response in a prior cycle, as what works for one patient may not work as well for another.

‍